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Brainstem neurons are initiators of neuritic plaques. 0 Comment(s)

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Description:
This hypothesis provides a mechanism for triggering the formation of the neuritic plaques in the brains of Alzheimer Disease (AD) patients, aiming to explain why and how these plaques form preferentially in specific brain regions, such as the cerebral cortex and the hippocampus. According to this hypothesis, plaques are nucleated by oligomeric Aβ seeds that form at the terminals of projections of brainstem neurons, which extend into lesion prone regions, such as the hippocampus and the cerebral cortex. Brainstem neurons, rather than neurons in the cerebral cortex or hippocampus, are prone to accumulation of oligomerized Aβ at the terminals of their processes.
Authors: Muresan Z Muresan V

Derived from:

Muresan, Zoia

Muresan, Virgil

Muresan Z, Muresan V
Seeding neuritic plaques from the distance: a possible role for brainstem neurons in the development of Alzheimer's disease pathology.
Neuro-degenerative diseases. 2008;5(3-4):250-3

Contains 26 Statements:
27 with evidence 0 without evidence and a total of: 96 citations ; Related to external statements: 13 consistent 2 inconsistent 0 discussed 3 with alternatives

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1. Neuritic plaques contain at their core extracellular deposits of Aβ peptide.
  SHOW Details Supporting(3) Consistent(5)
  Description: Neuritic plaques have a heterogeneous composition, and contain, in addition to Aβ, cellular and extracellular proteins, proteoglycans, metal ions. These are recruited to the plaques during their formation. However, the core of the neuritic plaques is composed of Aβ. Early plaques in AD brains, while containing oligomeric forms of Aβ, do not contain Aβ fibrils and have a diffuse appearance. While the plaque’s other components may play a role in plaque formation, it is thought that Aβ polymerization is essential for their development.
  Experimental Approach: Mechanism - biochemistry and structural biology,
  Pathogenic Narrative Tags: Pathologic change
  Supporting Evidence
  
  Atwood C, Martins R, Smith M, Perry G
  Senile plaque composition and posttranslational modification of amyloid-beta peptide and associated proteins.
  Peptides. 2002 Jul;23(7):1343-50
  
  Selkoe D
  Alzheimer's disease: genes, proteins, and therapy.
  Physiological reviews. 2001 Apr;81(2):741-66
  
  Murphy C, Wang S, Williams T, Weiss D, Solomon A
  Characterization of systemic amyloid deposits by mass spectrometry.
  Methods in enzymology. 2006;412:48-62
  
  Consistent statements
  
  In the aging and AD brain, Aβ, a 40-42 amino acid peptide, accumulates in the extracellular space as small deposits and senile plaques. Cotman C Su J
  
  The Aβ peptide was recognized as the primary component of AD plaques. Hardy J Selkoe D
  
  Aβ peptides are the major constituents of Alzheimer Disease brain plaques. Plant L Webster N Boyle J Ramsden M Freir D Peers C Pearson H
  
  The earliest pathological event that occurs in the process of AD is probably the deposition of insoluble forms of Aβ peptide in the brain. Holtzman D
  
  AD is identified by senile or amyloid plaques, neurofibrillary tangles and amyloid angiopathy accompanied by loss of synapses and neurons in neocortex and hippocampus.
2. The polymerization of soluble Aβ, which leads to plaque formation, is nucleated by “seeds” of oligomeric Aβ, but it remains unclear where seeds of polymerized Aβ originate or how they are formed.
  SHOW Details Supporting(9) Consistent(3)
  Description: Since plaques contain at their core Aβ aggregates, it was assumed that aggregation of Aβ is the key event in plaque formation. Since Aβ undergoes spontaneous aggregation only at concentrations much higher than the ~10 nM physiological concentration, it was postulated that Aβ aggregation in AD is facilitated by disease-specific factors. A different view is offered by the seeded polymerization hypothesis of Harper and Lansbury. According to them, polymerization of extracellular, soluble Aβ requires a “seed” of aggregated Aβ that serves to nucleate further polymerization. It was proposed that the seed may contain a modified Aβ species that has high propensity to aggregate, such as the GM1 ganglioside-bound Aβ. An altered APP metabolism or transport, or inefficient clearance of Aβ could also cause abnormal local accumulation of Aβ, and somehow “force” its aggregation. The fact that “seeds” of Aβ are present in AD brains and can efficiently nucleate plaques was elegantly shown in studies where amyloidogenesis was induced in APP transgenic mice by intracerebral injection of extracts from AD brains. Still, questions such as: What is the seed? Where does it come from? How is it formed? are unanswered, and are addressed by our hypothesis.
  Experimental Approach: Mechanism - biochemistry and structural biology, Mechanism - molecular and cell,
  Pathogenic Narrative Tags: Pathogenic event
  Supporting Evidence
  
  Zhang Q, Powers E, Nieva J, Huff M, Dendle M, Bieschke J, Glabe C, Eschenmoser A, Wentworth P, Lerner R, Kelly J
  Metabolite-initiated protein misfolding may trigger Alzheimer's disease.
  Proceedings of the National Academy of Sciences of the United States of America. 2004 Apr 6;101(14):4752-7
  
  Harper J, Lansbury P
  Models of amyloid seeding in Alzheimer's disease and scrapie: mechanistic truths and physiological consequences of the time-dependent solubility of amyloid proteins.
  Annual review of biochemistry. 1997;66:385-407
  
  Meyer-Luehmann M, Coomaraswamy J, Bolmont T, Kaeser S, Schaefer C, Kilger E, Neuenschwander A, Abramowski D, Frey P, Jaton A, Vigouret J, Paganetti P, Walsh D, Mathews P, Ghiso J, Staufenbiel M, Walker L, Jucker M
  Exogenous induction of cerebral beta-amyloidogenesis is governed by agent and host.
  Science (New York, N.Y.). 2006 Sep 22;313(5794):1781-4
  
  Hayashi H, Kimura N, Yamaguchi H, Hasegawa K, Yokoseki T, Shibata M, Yamamoto N, Michikawa M, Yoshikawa Y, Terao K, Matsuzaki K, Lemere C, Selkoe D, Naiki H, Yanagisawa K
  A seed for Alzheimer amyloid in the brain.
  The Journal of neuroscience : the official journal of the Society for Neuroscience. 2004 May 19;24(20):4894-902
  
  Mizuno T, Nakata M, Naiki H, Michikawa M, Wang R, Haass C, Yanagisawa K
  Cholesterol-dependent generation of a seeding amyloid beta-protein in cell culture.
  The Journal of biological chemistry. 1999 May 21;274(21):15110-4
  
  Lansbury P
  Structural neurology: are seeds at the root of neuronal degeneration?
  Neuron. 1997 Dec;19(6):1151-4
  
  Kane M, Lipinski W, Callahan M, Bian F, Durham R, Schwarz R, Roher A, Walker L
  Evidence for seeding of beta -amyloid by intracerebral infusion of Alzheimer brain extracts in beta -amyloid precursor protein-transgenic mice.
  The Journal of neuroscience : the official journal of the Society for Neuroscience. 2000 May 15;20(10):3606-11
  
  Kamal A, Almenar-Queralt A, LeBlanc J, Roberts E, Goldstein L
  Kinesin-mediated axonal transport of a membrane compartment containing beta-secretase and presenilin-1 requires APP.
  Nature. 2001 Dec 6;414(6864):643-8
  
  Bieschke J, Zhang Q, Powers E, Lerner R, Kelly J
  Oxidative metabolites accelerate Alzheimer's amyloidogenesis by a two-step mechanism, eliminating the requirement for nucleation.
  Biochemistry. 2005 Apr 5;44(13):4977-83
  
  Consistent statements
  
  Conversion of Aβ from a soluble form to fibrillar form occurs via “seeded” polymerization of Aβ40 and Aβ42. Holtzman D
  
  Aβ deposition is promoted by increased concentration of Aβ or increased rate of seeding. Golde T
  
  Amyloid increases through Aβ concentration-dependent seeded polymerization. Golde T
3. Neuritic plaques are relevant to AD.
  SHOW Details Supporting(11) Consistent(1)
  Description: Neuritic plaques have been considered as a probable cause of neuronal degeneration and death in AD long before the discovery that plaques contain Aβ. Since then, evidence has accumulated indicating that Aβ may be responsible – at least in part – for the pathology and symptoms of AD. It appeared that the oligomerization state of the peptide is highly relevant to Aβ toxicity. Aβ is generated from APP likely as monomer, while mature plaques contain Aβ fibrils, which form as a result of peptide aggregation. Between monomers and fibrils, there are many oligomeric forms – from dimers and trimers to Aβ-derived diffusible ligands (ADDLs), annular assemblies, and protofibrils (the latter forms being mainly the result of in vitro polymerization). Recent work has shown that it is the presence of the soluble Aβ oligomers (dimers, trimers, or higher oligomers, such as Aβ*56) rather than the fibrillar Aβ and the brain plaque load which correlates with the learning and memory deficits, in mouse models of AD. If the fibrillar Aβ present in mature plaques is less toxic than the oligomers, then are the neuritic plaques less relevant to AD pathology than the soluble Aβ oligomers? Not at all! Recent studies suggest that the plaques might function as reservoirs of the highly pathogenic, smaller Aβ oligomers, from which they can be released.
  Experimental Approach: Mechanism - biochemistry and structural biology,
  Pathogenic Narrative Tags: Pathologic change
  Supporting Evidence
  
  Walsh D, Klyubin I, Fadeeva J, Cullen W, Anwyl R, Wolfe M, Rowan M, Selkoe D
  Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo.
  Nature. 2002 Apr 4;416(6880):535-9
  
  Shankar G, Li S, Mehta T, Garcia-Munoz A, Shepardson N, Smith I, Brett F, Farrell M, Rowan M, Lemere C, Regan C, Walsh D, Sabatini B, Selkoe D
  Amyloid-beta protein dimers isolated directly from Alzheimer's brains impair synaptic plasticity and memory.
  Nature medicine. 2008 Aug;14(8):837-42
  
  LaFerla F, Green K, Oddo S
  Intracellular amyloid-beta in Alzheimer's disease.
  Nature reviews. Neuroscience. 2007 Jul;8(7):499-509
  
  Glenner G, Wong C
  Alzheimer's disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein.
  Biochemical and biophysical research communications. 1984 May 16;120(3):885-90
  
  Cleary J, Walsh D, Hofmeister J, Shankar G, Kuskowski M, Selkoe D, Ashe K
  Natural oligomers of the amyloid-beta protein specifically disrupt cognitive function.
  Nature neuroscience. 2005 Jan;8(1):79-84
  
  Lesné S, Koh M, Kotilinek L, Kayed R, Glabe C, Yang A, Gallagher M, Ashe K
  A specific amyloid-beta protein assembly in the brain impairs memory.
  Nature. 2006 Mar 16;440(7082):352-7
  
  Martins I, Kuperstein I, Wilkinson H, Maes E, Vanbrabant M, Jonckheere W, Van Gelder P, Hartmann D, D'Hooge R, De Strooper B, Schymkowitz J, Rousseau F
  Lipids revert inert Abeta amyloid fibrils to neurotoxic protofibrils that affect learning in mice.
  The EMBO journal. 2008 Jan 9;27(1):224-33
  
  Lambert M, Barlow A, Chromy B, Edwards C, Freed R, Liosatos M, Morgan T, Rozovsky I, Trommer B, Viola K, Wals P, Zhang C, Finch C, Krafft G, Klein W
  Diffusible, nonfibrillar ligands derived from Abeta1-42 are potent central nervous system neurotoxins.
  Proceedings of the National Academy of Sciences of the United States of America. 1998 May 26;95(11):6448-53
  
  Kamenetz F, Tomita T, Hsieh H, Seabrook G, Borchelt D, Iwatsubo T, Sisodia S, Malinow R
  APP processing and synaptic function.
  Neuron. 2003 Mar 27;37(6):925-37
  
  Haass C, Selkoe D
  Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer's amyloid beta-peptide.
  Nature reviews. Molecular cell biology. 2007 Feb;8(2):101-12
  
  Masters C, Simms G, Weinman N, Multhaup G, McDonald B, Beyreuther K
  Amyloid plaque core protein in Alzheimer disease and Down syndrome.
  Proceedings of the National Academy of Sciences of the United States of America. 1985 Jun;82(12):4245-9
  
  Consistent statements
  
  The invariant accumulation of insoluble amyloid plaques in AD may signify that they serve as relatively inert reservoirs of small bioactive oligomers, and they may disassemble more readily in the presence of lipids. Shankar G Li S Mehta T Garcia-Munoz A Shepardson N Smith I Brett F Farrell M Rowan M Lemere C Regan C Walsh D Sabatini B Selkoe D
4. Plaques form preferentially in specific brain regions, such as the cerebral cortex and the hippocampus.
  SHOW Details Supporting(1) Consistent(1)
  Description: Different regions of the AD brain are differentially affected by plaque pathology. Although APP is ubiquitously expressed, aggregation of Aβ, followed by incorporation into plaques occurs only in specific brain regions, such as the cerebral cortex and the hippocampus. What triggers plaque formation in certain brain regions and not in others is poorly understood, and our hypothesis addresses this problem.
  Experimental Approach: Mechanism - biochemistry and structural biology
  Pathogenic Narrative Tags: Pathologic change
  Supporting Evidence
  
  Selkoe D
  Alzheimer's disease: genes, proteins, and therapy.
  Physiological reviews. 2001 Apr;81(2):741-66
  
  Consistent statements
  
  AD is identified by senile or amyloid plaques, neurofibrillary tangles and amyloid angiopathy accompanied by loss of synapses and neurons in neocortex and hippocampus.
5. Cultured neuronal cells originating from the brainstem - but not neurons derived from the cerebral cortex or hippocampus - accumulate oligomerized Aβ at the terminals of their processes.
  SHOW Details Supporting(2) Consistent(1)
  Description: It is intriguing that, although studies done with cultured cortical and hippocampal neurons from APP transgenic mice have occasionally identified neuritic staining for Aβ, preferential accumulation at neurite terminals of large quantities of Aβ – as found by us in CAD cells – is rare. Our own work with primary cultures of cortical neurons from normal mice revealed that they occasionally contain cells that show Aβ accumulations, mainly in the cell body but also within neurites. Like in CAD cells, within neurites, the Aβ is detected as large puncta, reminiscent of late endosomes or autophagic vacuoles. Unlike CAD cells, the cortical neurons mostly lacked the heavy accumulation of Aβ at neurite terminals. Possibly, this is due to differences between neurons from different brain regions: CAD cells originate from locus coeruleus (LC) neurons in the brainstem, and may have different properties than cortical or hippocampal neurons. We note that, in situ, in mouse models of AD, oligomerized Aβ was occasionally detected at process terminals, but the origin of these processes was not determined.
  Experimental Approach: Mechanism - physiological systems, Animal models, Mechanism - biochemistry and structural biology
  Pathogenic Narrative Tags: Pathogenic event
  Supporting Evidence
  
  Fein J, Sokolow S, Miller C, Vinters H, Yang F, Cole G, Gylys K
  Co-localization of amyloid beta and tau pathology in Alzheimer's disease synaptosomes.
  The American journal of pathology. 2008 Jun;172(6):1683-92
  
  Takahashi R, Milner T, Li F, Nam E, Edgar M, Yamaguchi H, Beal M, Xu H, Greengard P, Gouras G
  Intraneuronal Alzheimer abeta42 accumulates in multivesicular bodies and is associated with synaptic pathology.
  The American journal of pathology. 2002 Nov;161(5):1869-79
  
  Consistent statements
  
  CAD cell are a useful model for studying a potential role of brainstem neurons in the initiation of neuritic plaques in Alzheimer’s disease. Muresan Z Muresan V
6. CAD cells are a useful model for studies of APP cell biology and Alzheimers disease pathology, including Aβ accumulation within neurites.
  SHOW Details Supporting(7)
  Description: This hypothesis describes the use of CAD cells as a model system to study the cell biology of APP, including its metabolism, intracellular transport, function, and implication in neuronal degeneration. CAD cells express the neuronal form of APP (APP695), a fraction of which is transported within neurites at velocities similar to those reported for cultured hippocampal neurons. Like in neurons, in CAD cells, APP is processed by secretase activities to generate sAPPs, Aβ, and CTFs - including the AICD (part of which is translocated into the nucleus). Both the full-length APP and the CTFs become phosphorylated – via multiple signaling pathways - at a critical threonine residue in the cytoplasmic domain (Thr668 in APP695). Aβ is produced intracellularly in CAD cells, and forms low- and high-number oligomers that occasionally accumulate at neurite terminals. Thus, an essential feature of the neuronal pathology thought to occur in Alzheimer’s disease can be reproduced – and studied - in CAD cells.
  Contained Discourse: 10 Elements
  Experimental Approach:
  Pathogenic Narrative Tags:
  Supporting Evidence
  
  Muresan Z, Muresan V
  Neuritic deposits of amyloid-beta peptide in a subpopulation of central nervous system-derived neuronal cells.
  Molecular and cellular biology. 2006 Jul;26(13):4982-97
  
  Muresan Z, Muresan V
  Seeding neuritic plaques from the distance: a possible role for brainstem neurons in the development of Alzheimer's disease pathology.
  Neuro-degenerative diseases. 2008;5(3-4):250-3
  
  Muresan Z, Muresan V
  A phosphorylated, carboxy-terminal fragment of beta-amyloid precursor protein localizes to the splicing factor compartment.
  Human molecular genetics. 2004 Mar 1;13(5):475-88
  
  Muresan Z, Muresan V
  Coordinated transport of phosphorylated amyloid-beta precursor protein and c-Jun NH2-terminal kinase-interacting protein-1.
  The Journal of cell biology. 2005 Nov 21;171(4):615-25
  
  Muresan Z, Muresan V
  The amyloid-beta precursor protein is phosphorylated via distinct pathways during differentiation, mitosis, stress, and degeneration.
  Molecular biology of the cell. 2007 Oct;18(10):3835-44
  
  Muresan Z, Muresan V
  c-Jun NH2-terminal kinase-interacting protein-3 facilitates phosphorylation and controls localization of amyloid-beta precursor protein.
  The Journal of neuroscience : the official journal of the Society for Neuroscience. 2005 Apr 13;25(15):3741-51
  
  Muresan V, Varvel N, Lamb B, Muresan Z
  The cleavage products of amyloid-beta precursor protein are sorted to distinct carrier vesicles that are independently transported within neurites.
  The Journal of neuroscience : the official journal of the Society for Neuroscience. 2009 Mar 18;29(11):3565-78
7. Neuritic accumulation of Aβ is restricted to a small population of neighboring cells, in CAD cell cultures.
  SHOW Details Supporting(1)
  Description: An interesting observation was that CAD cells that accumulate Aβ in their processes represent a small fraction of the total cells, and appear in islet-like clusters, segregated from the dominant, conventional cells. Since CAD cells divide when cultured in the presence of serum, it seems likely that the cells contained within each separate cluster originated from one, or a few cells prone to increased generation of Aβ. Alternatively, extrinsic factors that may randomly be generated in parts of the cell culture dish could trigger changes in the metabolism of a few cells, leading to abnormal APP processing and neuritic accumulation of Aβ. Non-homogeneities in the culture dish may arise in different ways, including local variation in cell density.
  Experimental Approach: Mechanism - molecular and cell,
  Pathogenic Narrative Tags: Initial condition
  Supporting Evidence
  
  Muresan Z, Muresan V
  Neuritic deposits of amyloid-beta peptide in a subpopulation of central nervous system-derived neuronal cells.
  Molecular and cellular biology. 2006 Jul;26(13):4982-97
8. Accumulation of Aβ begins within neurites, prior to any major signs of neurodegeneration or cell death, although the terminals that contain accumulations appear dystrophic.
  SHOW Details Supporting(1) Consistent(4)
  Description: Morphologically, CAD cells containing Aβ accumulations appear normal; they are not undergoing degeneration or cell death. Indeed, they do not reveal any detachment of their processes from the cell bodies (typical for a Wallerian-like degenerative process), nor do they show signs of plasmalemmal disintegration (typical for necrosis) or nuclear fragmentation (typical for apoptosis). However, their terminals appear somewhat distended.
  Experimental Approach: Mechanism - biochemistry and structural biology
  Pathogenic Narrative Tags: Pathogenic event
  Supporting Evidence
  
  Muresan Z, Muresan V
  Neuritic deposits of amyloid-beta peptide in a subpopulation of central nervous system-derived neuronal cells.
  Molecular and cellular biology. 2006 Jul;26(13):4982-97
  
  Consistent statements
  
  In parallel with characteristic AD pathology, Aβ induces the formation of dystrophic neurites in cultured neurons. Cotman C Su J
  
  Aβ induces local neurite degeneration referred to as neuritic apoptosis or synaptotosis which displays the morphological and biochemical characteristics of apoptosis. Thus neurite degeneration may use mechanisms common to apoptotsis. Cotman C
  
  Cell death in human AD brains is not well correlated with Alzheimer Disease progression. Dziewczapolski G Glogowski C Masliah E Heinemann S
  
  Imaging of neurite dystrophy and new plaque formation over time demonstrated that in the days after plaque formation, progressive neuritic alterations were evident: from a smooth bend around the new plaque to very tortuous changes identical in appearance to dystrophic neurites seen in Alzheimer’s disease Meyer-Luehmann M Spires-Jones T Prada C Garcia-Alloza M de Calignon A Rozkalne A Koenigsknecht-Talboo J Holtzman D Bacskai B Hyman B
9. CAD cells that accumulate Aβ show redistribution of β-secretase (BACE1) to the processes, where it co-localizes with Aβ.
  SHOW Details Supporting(7) Consistent(1) Genes/Proteins: (1)
  Description: CAD cells that contain Aβ accumulations within neurites also contain BACE1, the major β-secretase, at the same location, coincident with Aβ. The extent of BACE1 accumulation within the neuronal processes of these cells is abnormal, since this enzyme is normally localized to Golgi compartments and early endosomes in the cell body. This result suggests that, in vivo, mislocalization of BACE1 may cause the production and accumulation of Aβ within processes and synaptic regions. This result is in line with a recent report that proposes that BACE1 localization – in addition to its expression level - determines the amount of generated Aβ and its accumulation in plaques.
  Experimental Approach: Mechanism - biochemistry and structural biology, Mechanism - molecular and cell,
  Pathogenic Narrative Tags: Pathogenic event
  Supporting Evidence
  
  Fukumoto H, Cheung B, Hyman B, Irizarry M
  Beta-secretase protein and activity are increased in the neocortex in Alzheimer disease.
  Archives of neurology. 2002 Sep;59(9):1381-9
  
  Yan R, Han P, Miao H, Greengard P, Xu H
  The transmembrane domain of the Alzheimer's beta-secretase (BACE1) determines its late Golgi localization and access to beta -amyloid precursor protein (APP) substrate.
  The Journal of biological chemistry. 2001 Sep 28;276(39):36788-96
  
  Holsinger R, McLean C, Beyreuther K, Masters C, Evin G
  Increased expression of the amyloid precursor beta-secretase in Alzheimer's disease.
  Annals of neurology. 2002 Jun;51(6):783-6
  
  Yang L, Lindholm K, Yan R, Citron M, Xia W, Yang X, Beach T, Sue L, Wong P, Price D, Li R, Shen Y
  Elevated beta-secretase expression and enzymatic activity detected in sporadic Alzheimer disease.
  Nature medicine. 2003 Jan;9(1):3-4
  
  Muresan Z, Muresan V
  Neuritic deposits of amyloid-beta peptide in a subpopulation of central nervous system-derived neuronal cells.
  Molecular and cellular biology. 2006 Jul;26(13):4982-97
  
  Kinoshita A, Fukumoto H, Shah T, Whelan C, Irizarry M, Hyman B
  Demonstration by FRET of BACE interaction with the amyloid precursor protein at the cell surface and in early endosomes.
  Journal of cell science. 2003 Aug 15;116(Pt 16):3339-46
  
  Lee E, Zhang B, Liu K, Greenbaum E, Doms R, Trojanowski J, Lee V
  BACE overexpression alters the subcellular processing of APP and inhibits Abeta deposition in vivo.
  The Journal of cell biology. 2005 Jan 17;168(2):291-302
  
  Consistent statements
  
  Aβ induces local neurite degeneration referred to as neuritic apoptosis or synaptotosis which displays the morphological and biochemical characteristics of apoptosis. Thus neurite degeneration may use mechanisms common to apoptotsis. Cotman C
  
  Genes/Proteins
  
  Protein: Beta-secretase 1 [Mus musculus]
10. Neuritic Aβ accumulations co-localize with markers of late endosomes and autophagic vacuoles.
  SHOW Details Supporting(2) Consistent(1)
  Description: Results of co-localization with early endosomal markers and uptake experiments clearly showed that the neuritic Aβ does not accumulate in early endosomes, which are concentrated in the cell body region. It is likely that the neuritic Aβ is contained in late endosomes, such as multivesicular bodies, that originated by maturation from early endosomes generated in the cell body, and were then transported anterogradely, into the processes. This hypothesis is supported by our data of co-localization with late endosomal markers, and is consistent with recent reports that identify the intraneuritic compartments that contain Aβ in neurons as multivesicular bodies. Alternatively, the Aβ could be contained in autophagic vacuoles that form within the neurites. Indeed, a recent study showed that macroautophagy may be an important pathway for Aβ generation in AD. Although not yet described in CAD cells, macroautophagy might be selectively triggered in some of these cells, ultimately leading to the abnormal generation and accumulation of Aβ.
  Experimental Approach: Mechanism - biochemistry and structural biology, Mechanism - molecular and cell, Pathophysiology
  Pathogenic Narrative Tags: Pathogenic event
  Supporting Evidence
  
  Yu W, Cuervo A, Kumar A, Peterhoff C, Schmidt S, Lee J, Mohan P, Mercken M, Farmery M, Tjernberg L, Jiang Y, Duff K, Uchiyama Y, Näslund J, Mathews P, Cataldo A, Nixon R
  Macroautophagy--a novel Beta-amyloid peptide-generating pathway activated in Alzheimer's disease.
  The Journal of cell biology. 2005 Oct 10;171(1):87-98
  
  Takahashi R, Milner T, Li F, Nam E, Edgar M, Yamaguchi H, Beal M, Xu H, Greengard P, Gouras G
  Intraneuronal Alzheimer abeta42 accumulates in multivesicular bodies and is associated with synaptic pathology.
  The American journal of pathology. 2002 Nov;161(5):1869-79
  
  Consistent statements
  
  Earliest Aβ 40 and 42 peptides accumulate within intracellular membranous compartments such as endosomes or lysosomes. Marchesi V
11. Processes containing Aβ accumulations contain fewer mitochondria than processes lacking Aβ accumulations.
  SHOW Details Supporting(5) Consistent(1)
  Description: Transport and neuritic localization of mitochondria is evidently perturbed in CAD cells that contain Aβ accumulations. This could be a consequence of the neuritically accumulated Aβ. Alternatively, mitochondrial mislocalization may itself cause the accumulation of Aβ. Mitochondrial dysfunction may indeed play a role in AD pathogenesis; this was linked to the oxidative damage, which occurs before plaque pathology is detected. Our data suggest an alternative way for mitochondrial dysfunction in AD, caused by their deficient transport and localization. This could result in diminished supply of ATP to the neurites, and perturbation of APP metabolism. Interestingly, several proteins relevant to AD, including APP and the secretases, were shown to also localize to mitochondria.
  Experimental Approach: Mechanism - molecular and cell, Pathophysiology, Mechanism - biochemistry and structural biology
  Pathogenic Narrative Tags: Pathogenic event
  Supporting Evidence
  
  Muresan Z, Muresan V
  Seeding neuritic plaques from the distance: a possible role for brainstem neurons in the development of Alzheimer's disease pathology.
  Neuro-degenerative diseases. 2008;5(3-4):250-3
  
  Lin M, Beal M
  Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases.
  Nature. 2006 Oct 19;443(7113):787-95
  
  Anandatheerthavarada H, Biswas G, Robin M, Avadhani N
  Mitochondrial targeting and a novel transmembrane arrest of Alzheimer's amyloid precursor protein impairs mitochondrial function in neuronal cells.
  The Journal of cell biology. 2003 Apr 14;161(1):41-54
  
  Lustbader J, Cirilli M, Lin C, Xu H, Takuma K, Wang N, Caspersen C, Chen X, Pollak S, Chaney M, Trinchese F, Liu S, Gunn-Moore F, Lue L, Walker D, Kuppusamy P, Zewier Z, Arancio O, Stern D, Yan S, Wu H
  ABAD directly links Abeta to mitochondrial toxicity in Alzheimer's disease.
  Science (New York, N.Y.). 2004 Apr 16;304(5669):448-52
  
  Hansson C, Frykman S, Farmery M, Tjernberg L, Nilsberth C, Pursglove S, Ito A, Winblad B, Cowburn R, Thyberg J, Ankarcrona M
  Nicastrin, presenilin, APH-1, and PEN-2 form active gamma-secretase complexes in mitochondria.
  The Journal of biological chemistry. 2004 Dec 3;279(49):51654-60
  
  Consistent statements
  
  Formation of Aβ ion channels in the mitochondrial membranes may disrupt mitochondrial membrane potential impairing energy production and leading to apoptosis. Smith I Green K LaFerla F
12. Mitochondria may undergo autophagocytosis in CAD cells affected by Aβ accumulation.
  SHOW Details Supporting(1) Consistent(2) Alternative to: (1)
  Description: Co-localization data revealed that the mitochondria-specific antigen, lipoic acid, when detected in affected neurites, co-localizes to a large extent with the Aβ accumulations. Since deficient mitochondria are usually eliminated by autophagy, and because the Aβ accumulations stain for markers of autophagy, this result may indicate that mitochondrial autophagy is increased in Aβ accumulating cells, and that the observed mitochondrial paucity and the formation of the Aβ accumulations are related processes. This interpretation of our data is in line with recent reports showing that autophagic degradation of mitochondria is increased in AD. How would the above-described scenario explain the presence of Aβ oligomers in autophagic vacuoles that also contain the mitochondrial debris? APP and Aβ have been reported to be present in mitochondria, and this might be a source for some of the Aβ accumulations that we detect within CAD cell neurites.
  Experimental Approach: Mechanism - molecular and cell, Pathophysiology, Mechanism - biochemistry and structural biology
  Pathogenic Narrative Tags: Pathologic change
  Supporting Evidence
  
  Moreira P, Siedlak S, Wang X, Santos M, Oliveira C, Tabaton M, Nunomura A, Szweda L, Aliev G, Smith M, Zhu X, Perry G
  Autophagocytosis of mitochondria is prominent in Alzheimer disease.
  Journal of neuropathology and experimental neurology. 2007 Jun;66(6):525-32
  
  Consistent statements
  
  Caspase activation and apoptosis may be initiated following insertion of Aβ channels into specific neuronal organelles such as the ER or mitochondria. Smith I Green K LaFerla F
  
  Formation of Aβ ion channels in the mitochondrial membranes may disrupt mitochondrial membrane potential impairing energy production and leading to apoptosis. Smith I Green K LaFerla F
  
  Alternative statements
  
  Autophagy, an additional potential link between senescence and neurodegeneration, has been implicated in AD and many other neurodegenerative conditions, since genetic removal of autophagy genes results in neurodegeneration, and genetic alterations that induce premature aging phenotypes are associated with autophagy induction. Golde T Miller V
13. Autophagocytosis in CAD cells may also target dense-core vesicles.
  SHOW Details Supporting(2)
  Description: It is likely that the conditions that cause mitochondrial autophagy also cause autophagocytosis of other organelles, including transport vesicles that contain APP. Oxidative stress is likely to affect secretory vesicles in catecholaminergic neurons, such as the CAD cells. Indeed, the large, dense-core vesicles present in such cells have been shown to also contain iron, and a perturbation of the iron homeostasis in these vesicles may trigger their autophagocytosis. Autophagy has been previously proposed to modulate secretion in some cells. Interestingly, dense-core vesicles accumulate in CAD cells (and other catecholaminergic cells) at the distal ends of their processes, at locations where Aβ accumulations are detected.
  Experimental Approach: Mechanism - molecular and cell, Pathophysiology,
  Pathogenic Narrative Tags: Pathogenic event
  Supporting Evidence
  
  MacGregor R, Bansal D
  Inhibitors of cellular proteolysis cause increased secretion from parathyroid cells.
  Biochemical and biophysical research communications. 1989 May 15;160(3):1339-43
  
  Ortega R, Cloetens P, Devès G, Carmona A, Bohic S
  Iron storage within dopamine neurovesicles revealed by chemical nano-imaging.
  PLoS ONE. 2007;2(9):e925
14. An increased level of APP, or increased processing of APP is unlikely to be the cause of the neuritic Aβ accumulations.
  SHOW Details Supporting(1)
  Description: Why some CAD cells show neuritic Aβ accumulations while most of the others do not could be explained by an increased processing of APP within neurites (i.e., during transport of APP), as suggested by previous data. Indeed, cultured CAD cells and primary neurons occasionally show increased levels of neuritic Aβ, and the intracellular distribution of APP-derived polypeptides differs among individual cells, suggesting that APP may be processed differently in otherwise similar cells. However, in such cases, we did not see accumulation of Aβ at specific places along the neurites (or at their terminals). Rather, Aβ was relatively homogeneously distributed throughout these neurites. Thus, we do not think that an increased level of APP, or increased processing of APP is the cause of the neuritic Aβ accumulations.
  Experimental Approach: Pathophysiology, Mechanism - biochemistry and structural biology
  Pathogenic Narrative Tags: Perturbation
  Supporting Evidence
  
  Kamal A, Almenar-Queralt A, LeBlanc J, Roberts E, Goldstein L
  Kinesin-mediated axonal transport of a membrane compartment containing beta-secretase and presenilin-1 requires APP.
  Nature. 2001 Dec 6;414(6864):643-8
15. Intracellular stress may lead to the initiation of Aβ oligomerization and accumulation.
  SHOW Details Supporting(2) Consistent(2) Alternative to: (1)
  Description: Genotoxic stress and cellular stress trigger a variety of cellular responses, ranging from subtle modifications of protein composition to apoptosis. The alteration of the localization of BACE1 and mitochondria, and the accumulation of Aβ within the neurites, could be the result of stress. Oxidative stress and hypoxia are among the most likely stress forms that may lead to Aβ accumulation in CAD cells.
  Experimental Approach: Mechanism - molecular and cell, Mechanism - biochemistry and structural biology, Pathophysiology
  Pathogenic Narrative Tags: Pathogenic event
  Supporting Evidence
  
  Bredesen D, Rao R, Mehlen P
  Cell death in the nervous system.
  Nature. 2006 Oct 19;443(7113):796-802
  
  Barnham K, Masters C, Bush A
  Neurodegenerative diseases and oxidative stress.
  Nature reviews. Drug discovery. 2004 Mar;3(3):205-14
  
  Consistent statements
  
  Aβ accumulation is the initial step that triggers all AD related pathologies, including accumulation of tau or synuclein, inflammatory response, oxidative stress, neuronal dysfunction and dementia. Golde T
  
  Intracellular Aβ has been implicated in the pathogenesis of AD, including its relationship to extracellular amyloid plaques as well as deleterious effects on synaptic function and learning and memory. Dziewczapolski G Glogowski C Masliah E Heinemann S
  
  Alternative statements
  
  Aβ oxidizes membrane cholesterol, liberates H₂O₂ and increases oxidative stress.
16. Neurons that show Aβ accumulations may attempt to reenter the cell cycle.
  SHOW Details Supporting(3) Consistent(5) Inconsistent(1) Alternative to: (1)
  Description: CAD cells that show the Aβ accumulations clearly have something in common. One possibility is that the neuritic Aβ phenotype could result from a failed attempt of neurons to re-enter the cell cycle. Recent work indicates that in AD brains, as well as in mouse models of AD, ectopic initiation of cell-cycle processes in neurons is an early sign of neuronal distress and increased vulnerability to insults. Although Aβ accumulating cells are only found in cultures maintained under differentiating conditions, they are in fact detectable very early after switching to differentiating conditions, when some cells may still attempt to undergo mitosis. This possibility remains to be tested.
  Experimental Approach: Pathophysiology, Mechanism - molecular and cell
  Pathogenic Narrative Tags: Pathogenic event
  Supporting Evidence
  
  Yang Y, Varvel N, Lamb B, Herrup K
  Ectopic cell cycle events link human Alzheimer's disease and amyloid precursor protein transgenic mouse models.
  The Journal of neuroscience : the official journal of the Society for Neuroscience. 2006 Jan 18;26(3):775-84
  
  Kallhoff-Munoz V, Hu L, Chen X, Pautler R, Zheng H
  Genetic dissection of gamma-secretase-dependent and -independent functions of presenilin in regulating neuronal cell cycle and cell death.
  The Journal of neuroscience : the official journal of the Society for Neuroscience. 2008 Oct 29;28(44):11421-31
  
  Varvel N, Bhaskar K, Patil A, Pimplikar S, Herrup K, Lamb B
  Abeta oligomers induce neuronal cell cycle events in Alzheimer's disease.
  The Journal of neuroscience : the official journal of the Society for Neuroscience. 2008 Oct 22;28(43):10786-93
  
  Consistent statements
  
  It is possible that LC neurons that show CCEs have their projections in the hippocampus and cortex, where plaques are regularly found. Muresan Z Muresan V
  
  Several reports describe aberrant regulation of cell cycle factors in AD brain. Suzuki T
  
  Neurons that show CCE do not retract their processes before doing so. Muresan Z Muresan V
  
  Inappropriate reactivation of the cell cycle is an early and important event in the development of Alzheimer disease. Vincent I Rosado M Davies P
  
  Aβ oligomers induce neuronal cell cycle events in Alzheimer disease. Varvel N Bhaskar K Patil A Pimplikar S Herrup K Lamb B
  
  Inconsistent statements
  
  Neuronal cell cycle events (CCEs) are also observed in the locus ceruleus and dorsal raphe at 8 months in the R1.40 mice, two brain regions in which no Aβ deposition is observed even at late ages. Varvel N Bhaskar K Patil A Pimplikar S Herrup K Lamb B
  
  Alternative statements
  
  Cortical cell cycle events (CCEs) appear ~8 months before the onset of fibrillar Aβ deposition in the B6- R1.40 model suggesting that fibrillar Aβ deposits are not responsible for the induction of neuronal CCEs and instead implicates either unique soluble Aβ species or particular APP processing products. Varvel N Bhaskar K Patil A Pimplikar S Herrup K Lamb B
17. The composition of the Aβ accumulations is complex, and includes many species of Aβ oligomers.
  SHOW Details Supporting(2) Consistent(4)
  Description: The use of the monoclonal antibody 6E10 (raised against human Aβ) to detect the neuritic Aβ accumulations in the mouse cell line, CAD may be of some concern, since the epitope recognized by this antibody lies within a region that is not fully conserved between humans and mice. However, the 6E10 antibody cross-reacts with mouse Aβ, when it is present at high concentration, both in immunocytochemistry and Western blots. Moreover, characterization of the 6E10-immunoreactive material in CAD cells with a series of other antibodies to Aβ, and antibodies to different regions of APP, confirmed that it contained bona fide Aβ and not the full length APP, sAPPs, or CTFs. Using carboxy-terminal-end antibodies to Aβ species, we showed that the neuritically accumulated material contains both Aβ40 and Aβ42. Cross-reactivity of the accumulations with an anti-oligomer antibody (A11) indicated that they include high-number oligomeric species. However, the accumulations also include low-number Aβ oligomers detectable in Western blots as dimers and trimers.
  Experimental Approach: Mechanism - biochemistry and structural biology,
  Pathogenic Narrative Tags: Pathologic change
  Supporting Evidence
  
  Kayed R, Head E, Thompson J, McIntire T, Milton S, Cotman C, Glabe C
  Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis.
  Science (New York, N.Y.). 2003 Apr 18;300(5618):486-9
  
  Muresan Z, Muresan V
  Neuritic deposits of amyloid-beta peptide in a subpopulation of central nervous system-derived neuronal cells.
  Molecular and cellular biology. 2006 Jul;26(13):4982-97
  
  Consistent statements
  
  Prefibrillar Aβ assemblies may be neurotoxic in vivo. Hardy J Selkoe D
  
  Several lines of evidence indicate that smaller Aβ oligomers, rather than full-fledged fibrils, may be the primary neurotoxic form. Tycko R
  
  A form of oligomeric soluble Aβ may be the neurotoxic species, and ApoE may facilitate the formation of these species. Holtzman D
  
  AD diffusible ligands (ADDLs) or protofibrils cause injury to cultured neurons. Hardy J Selkoe D
18. Plaque initiation in AD may occur in two steps: increased accumulation of Aβ and formation of seeds.
  SHOW Details Supporting(1)
  Description: We envision a pathogenic process that occurs in two steps. One is the above-described formation of seeds at the neurite terminals of brainstem neurons that project into the lesion-prone brain regions. The second is an increased accumulation of soluble Aβ in the extracellular space, in these brain regions. This increased accumulation of extracellular Aβ could be the result of either an increased production/secretion, or a decreased clearance of the Aβ. Plaques would thus form when these two conditions are simultaneously met.
  Experimental Approach: Mechanism - molecular and cell, Mechanism - biochemistry and structural biology, Pathophysiology
  Pathogenic Narrative Tags: Pathogenic event
  Supporting Evidence
  
  Muresan Z, Muresan V
  Seeding neuritic plaques from the distance: a possible role for brainstem neurons in the development of Alzheimer's disease pathology.
  Neuro-degenerative diseases. 2008;5(3-4):250-3
19. Intracellular, neuritic Aβ accumulations occasionally become extracellular either by cell death or via exosomes.
  SHOW Details Supporting(2)
  Description: How could the intracellular Aβ accumulations become extracellular and serve as seeds for Aβ deposition? This could occur by fusion of the Aβ-containing autophagosomes and late endosomes (such as multivesicular bodies) with the plasma membrane. Alternatively, this could be the result of neurite degeneration and decomposition. Our immunocytochemistry data show the occasional presence of what could be neuritic debris containing Aβ. Whether these are true debris, or exosomes, generated by fusion with the plasma membrane of multivesicular bodies remains to be determined. Previous studies have identified the exosome as possible way of release of Aβ in the extracellular space.
  Experimental Approach: Mechanism - molecular and cell, Pathophysiology, Mechanism - biochemistry and structural biology
  Pathogenic Narrative Tags: Pathogenic event
  Supporting Evidence
  
  Muresan Z, Muresan V
  Seeding neuritic plaques from the distance: a possible role for brainstem neurons in the development of Alzheimer's disease pathology.
  Neuro-degenerative diseases. 2008;5(3-4):250-3
  
  Rajendran L, Honsho M, Zahn T, Keller P, Geiger K, Verkade P, Simons K
  Alzheimer's disease beta-amyloid peptides are released in association with exosomes.
  Proceedings of the National Academy of Sciences of the United States of America. 2006 Jul 25;103(30):11172-7
20. Neurons from different brain regions may show different properties pertinent to APP metabolism and susceptibility to Aβ.
  SHOW Details Supporting(4)
  Description: Why should CAD cells be more prone to neuritic Aβ accumulation than other cultured neurons? One possibility is that the observed effects are related to the fact that CAD cells are a cell line, not primary neurons. Yet, such phenotype was not reported for other neuronal cell lines. It is more likely that this propensity of CAD cells is due to an intrinsic, specific feature of neurons from the locus coeruleus that was maintained in CAD cells but is absent from neurons from other brain regions. The mammalian CNS contains hundreds of neuronal subtypes with different translational profiles and biological properties. Recent reports have shown that neurons from different regions of the brain have different susceptibility to the toxic effects of Aβ, which clearly suggests that “an intrinsic underlying biology” drives this different behavior. Yet, future studies will have to confirm that neuritic Aβ accumulation occurs in primary neurons from the locus coeruleus, as well as in the brain in situ, particularly in animal models of disease.
  Experimental Approach: Mechanism - molecular and cell
  Pathogenic Narrative Tags: Initial condition
  Supporting Evidence
  
  Emery B, Barres B
  Unlocking CNS cell type heterogeneity.
  Cell. 2008 Nov 14;135(4):596-8
  
  Romito-DiGiacomo R, Menegay H, Cicero S, Herrup K
  Effects of Alzheimer's disease on different cortical layers: the role of intrinsic differences in Abeta susceptibility.
  The Journal of neuroscience : the official journal of the Society for Neuroscience. 2007 Aug 8;27(32):8496-504
  
  Heiman M, Schaefer A, Gong S, Peterson J, Day M, Ramsey K, Suárez-Fariñas M, Schwarz C, Stephan D, Surmeier D, Greengard P, Heintz N
  A translational profiling approach for the molecular characterization of CNS cell types.
  Cell. 2008 Nov 14;135(4):738-48
  
  Doyle J, Dougherty J, Heiman M, Schmidt E, Stevens T, Ma G, Bupp S, Shrestha P, Shah R, Doughty M, Gong S, Greengard P, Heintz N
  Application of a translational profiling approach for the comparative analysis of CNS cell types.
  Cell. 2008 Nov 14;135(4):749-62
21. The locus coeruleus in the brainstem is largely affected by neuronal distress and cell death early in AD.
  SHOW Details Supporting(7) Inconsistent(1)
  Description: Although the neurons in the locus coeruleus die massively in AD, the prevailing view was that neuronal loss in the locus coeruleus is caused by the cortical Aβ, which “poisons” the projections of brainstem cells. This view is prevalent because this brain region mostly lacks neuritic plaques, both in humans and animal models of AD.
  Experimental Approach: Mechanism - molecular and cell, Mechanism - biochemistry and structural biology, Pathophysiology
  Pathogenic Narrative Tags: Pathogenic event
  Supporting Evidence
  
  Braak H, Braak E
  Frequency of stages of Alzheimer-related lesions in different age categories.
  Neurobiology of aging. 1997;18(4):351-7
  
  German D, Manaye K, White C, Woodward D, McIntire D, Smith W, Kalaria R, Mann D
  Disease-specific patterns of locus coeruleus cell loss.
  Annals of neurology. 1992 Nov;32(5):667-76
  
  Varvel N, Bhaskar K, Patil A, Pimplikar S, Herrup K, Lamb B
  Abeta oligomers induce neuronal cell cycle events in Alzheimer's disease.
  The Journal of neuroscience : the official journal of the Society for Neuroscience. 2008 Oct 22;28(43):10786-93
  
  Mann D, Yates P, Hawkes J
  The pathology of the human locus ceruleus.
  Clinical neuropathology. 1983;2(1):1-7
  
  Mann D, Yates P, Hawkes J
  Plaques and tangles and transmitter deficiencies in dementia.
  Journal of neurology, neurosurgery, and psychiatry. 1982 Jun;45(6):563-4
  
  Zweig R, Ross C, Hedreen J, Steele C, Cardillo J, Whitehouse P, Folstein M, Price D
  The neuropathology of aminergic nuclei in Alzheimer's disease.
  Annals of neurology. 1988 Aug;24(2):233-42
  
  German D, Nelson O, Liang F, Liang C, Games D
  The PDAPP mouse model of Alzheimer's disease: locus coeruleus neuronal shrinkage.
  The Journal of comparative neurology. 2005 Nov 28;492(4):469-76
  
  Inconsistent statements
  
  Cell death in human AD brains is not well correlated with Alzheimer Disease progression. Dziewczapolski G Glogowski C Masliah E Heinemann S
22. AD pathology may actually start in the brainstem. Catecholaminergic neurons of the locus coeruleus may play a role in AD pathobiology.
  SHOW Details Supporting(5)
  Description: This idea is in line with earlier – and possibly forgotten - reports suggesting that, in AD, pathologic alterations in the locus coeruleus may spread to cortical and hippocampal brain regions. Without describing specific mechanisms, these earlier reports point to the pathological changes in the cerebral cortex and hippocampus of AD brains as being the result of neuronal degeneration in the locus coeruleus, suggesting that AD is an anterograde degeneration, originating in the brainstem. More recent studies indicate that the locus coeruleus shows features of neuronal distress long before detectable Aβ deposition is detected in a mouse model of AD, and that locus coeruleus degeneration promotes AD pathogenesis in a mouse model of disease.
  Experimental Approach: Mechanism - molecular and cell, Pathophysiology, Mechanism - biochemistry and structural biology,
  Pathogenic Narrative Tags: Pathogenic event
  Supporting Evidence
  
  Saper C, Wainer B, German D
  Axonal and transneuronal transport in the transmission of neurological disease: potential role in system degenerations, including Alzheimer's disease.
  Neuroscience. 1987 Nov;23(2):389-98
  
  Heneka M, Ramanathan M, Jacobs A, Dumitrescu-Ozimek L, Bilkei-Gorzo A, Debeir T, Sastre M, Galldiks N, Zimmer A, Hoehn M, Heiss W, Klockgether T, Staufenbiel M
  Locus ceruleus degeneration promotes Alzheimer pathogenesis in amyloid precursor protein 23 transgenic mice.
  The Journal of neuroscience : the official journal of the Society for Neuroscience. 2006 Feb 1;26(5):1343-54
  
  Mann D, Yates P, Hawkes J
  The pathology of the human locus ceruleus.
  Clinical neuropathology. 1983;2(1):1-7
  
  Varvel N, Bhaskar K, Patil A, Pimplikar S, Herrup K, Lamb B
  Abeta oligomers induce neuronal cell cycle events in Alzheimer's disease.
  The Journal of neuroscience : the official journal of the Society for Neuroscience. 2008 Oct 22;28(43):10786-93
  
  Hertz L
  Is Alzheimer's disease an anterograde degeneration, originating in the brainstem, and disrupting metabolic and functional interactions between neurons and glial cells?
  Brain research. Brain research reviews. 1989;14(4):335-53
23. The locus coeruleus is affected by tau pathology (presence of neurofibrillary tangles) in AD.
  SHOW Details Supporting(2)
  Description: Neurons in the locus coeruleus die massively in AD and Down’s syndrome. While neuritic plaques are usually not found in this brain region, neurofibrillary tangles are present.
  Experimental Approach: Mechanism - biochemistry and structural biology,
  Pathogenic Narrative Tags: Pathologic change
  Supporting Evidence
  
  Mann D, Yates P, Hawkes J
  Plaques and tangles and transmitter deficiencies in dementia.
  Journal of neurology, neurosurgery, and psychiatry. 1982 Jun;45(6):563-4
  
  Zweig R, Ross C, Hedreen J, Steele C, Cardillo J, Whitehouse P, Folstein M, Price D
  The neuropathology of aminergic nuclei in Alzheimer's disease.
  Annals of neurology. 1988 Aug;24(2):233-42
24. The locus coeruleus is a target for other neurological disorders besides AD, including schizophrenia.
  SHOW Details Supporting(5)
  Description: The noradrenergic locus coeruleus is involved in the control of complex behavior, including arousal, alertness, as well as cognitive and endocrine functions. As such, the locus coeruleus is a target in many psychiatric and neurodegenerative disorders, including schizophrenia.
  Experimental Approach: Mechanism - molecular and cell,
  Pathogenic Narrative Tags: Initial condition
  Supporting Evidence
  
  Orellana Vidal G
  [Locus coeruleus: implications for psychiatry]
  Acta psiquiátrica y psicológica de América latina. 1995 Mar;41(1):57-66
  
  Craven R, Priddle T, Crow T, Esiri M
  The locus coeruleus in schizophrenia: a postmortem study of noradrenergic neurones.
  Neuropathology and applied neurobiology. 2005 Apr;31(2):115-26
  
  Grimm J, Mueller A, Hefti F, Rosenthal A
  Molecular basis for catecholaminergic neuron diversity.
  Proceedings of the National Academy of Sciences of the United States of America. 2004 Sep 21;101(38):13891-6
  
  Nilsson L, Schwieler L, Engberg G, Linderholm K, Erhardt S
  Activation of noradrenergic locus coeruleus neurons by clozapine and haloperidol: involvement of glutamatergic mechanisms.
  The international journal of neuropsychopharmacology / official scientific journal of the Collegium Internationale Neuropsychopharmacologicum (CINP). 2005 Sep;8(3):329-39
  
  Aston-Jones G, Cohen J
  An integrative theory of locus coeruleus-norepinephrine function: adaptive gain and optimal performance.
  Annual review of neuroscience. 2005;28:403-50
25. Intracellular determinants may confer the Aβ phenotype of CAD cells.
  SHOW Details Supporting(2)
  Description: Intracellular determinants conferring the Aβ phenotype would be clonally transmitted to the progenitors of a few cells that exhibit the biochemical and neuropathological features of neurons in AD brains. These intracellular determinants are not necessarily genetically inherited. As recently shown, gene expression in neurons could be spontaneously altered by L1 retrotransposition, resulting in neuronal somatic mosaicism, a phenomenon seen both in cultured neurons and in the brains of adult transgenic mice, in vivo. Thus, events triggering Aβ oligomerization and accumulation may be initiated randomly within single cells. Overall, our data may suggest that intracellular determinants, present in a small number of neurons, may contribute to the onset of Aβ oligomerization in AD.
  Experimental Approach:
  Pathogenic Narrative Tags:
  Supporting Evidence
  
  Glabe C
  Intracellular mechanisms of amyloid accumulation and pathogenesis in Alzheimer's disease.
  Journal of molecular neuroscience : MN. 2001 Oct;17(2):137-45
  
  Muotri A, Chu V, Marchetto M, Deng W, Moran J, Gage F
  Somatic mosaicism in neuronal precursor cells mediated by L1 retrotransposition.
  Nature. 2005 Jun 16;435(7044):903-10
26. Extracellular determinants may confer the Aβ phenotype of CAD cells.
  SHOW Details Supporting(2)
  Description: While intracellular determinants may explain the clustered appearance of Aβ accumulating cells, this could also be explained if the composition of the culture medium changes locally, in a limited area of the culture dish. Non-uniform culture conditions may arise spontaneously: one cell may die, and release factors that influence neighboring cells; cells may distribute non-uniformly and generate high cellular density in certain regions of the culture dish, leading to accumulation in the extracellular medium of secreted factors. In the in vivo brain, local variation in the composition of the extracellular medium may arise in many ways, including through secretion of factors by endothelial and glial cells.
  Experimental Approach: Mechanism - molecular and cell,
  Pathogenic Narrative Tags: Perturbation
  Supporting Evidence
  
  Dugas J, Mandemakers W, Rogers M, Ibrahim A, Daneman R, Barres B
  A novel purification method for CNS projection neurons leads to the identification of brain vascular cells as a source of trophic support for corticospinal motor neurons.
  The Journal of neuroscience : the official journal of the Society for Neuroscience. 2008 Aug 13;28(33):8294-305
  
  Barres B
  The mystery and magic of glia: a perspective on their roles in health and disease.
  Neuron. 2008 Nov 6;60(3):430-40
27. Brainstem neurons, as initiators of senile plaques, have relevance for AD therapeutics and drug discovery.
  SHOW Details Supporting(6)
  Description: By pointing to a specific group of neurons (from the brainstem) as initiators of senile plaques, our hypothesis may offer a novel perspective on AD pathogenesis. The neuronal cell system that is used in our studies is ideally suited for screening of compounds that may be good candidates for prevention of formation of senile plaques, and could potentially be used to treat brainstem neurons in early phases of AD.
  Experimental Approach: Target validation, Mechanism - biochemistry and structural biology, Pathophysiology
  Pathogenic Narrative Tags: Pathogenic event
  Supporting Evidence
  
  Muresan Z, Muresan V
  Neuritic deposits of amyloid-beta peptide in a subpopulation of central nervous system-derived neuronal cells.
  Molecular and cellular biology. 2006 Jul;26(13):4982-97
  
  Muresan Z, Muresan V
  c-Jun NH2-terminal kinase-interacting protein-3 facilitates phosphorylation and controls localization of amyloid-beta precursor protein.
  The Journal of neuroscience : the official journal of the Society for Neuroscience. 2005 Apr 13;25(15):3741-51
  
  Muresan Z, Muresan V
  Coordinated transport of phosphorylated amyloid-beta precursor protein and c-Jun NH2-terminal kinase-interacting protein-1.
  The Journal of cell biology. 2005 Nov 21;171(4):615-25
  
  Muresan Z, Muresan V
  A phosphorylated, carboxy-terminal fragment of beta-amyloid precursor protein localizes to the splicing factor compartment.
  Human molecular genetics. 2004 Mar 1;13(5):475-88
  
  Muresan Z, Muresan V
  Seeding neuritic plaques from the distance: a possible role for brainstem neurons in the development of Alzheimer's disease pathology.
  Neuro-degenerative diseases. 2008;5(3-4):250-3
  
  Muresan Z, Muresan V
  The amyloid-beta precursor protein is phosphorylated via distinct pathways during differentiation, mitosis, stress, and degeneration.
  Molecular biology of the cell. 2007 Oct;18(10):3835-44
Cites Life Science Entity:
- Protein: Beta-secretase 1 [Mus musculus]
Consistent with:
- CAD cell are a useful model for studying a potential role of brainstem neurons in the initiation of neuritic plaques in Alzheimer’s disease.
Curated by: Wong G
Created On: Mon, Jul 13 2009 11:53:56 EDT
Last Modified On: Mon Jul 13 11:53:59 EDT 2009

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