Alzheimer's disease pathophysiology: Difference between revisions

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*[[Chromosomal]] factors
*[[Chromosomal]] factors
==Pathogenesis==
==Pathogenesis==
The [[pathogenesis]] of Alzheimer's dementia (AD) can be explained by four [[pathological]] processes. The processes involved in the development of AD and their [[molecular]] basis is as follows:<ref name="pmid20413653">{{cite journal |vauthors=Crews L, Masliah E |title=Molecular mechanisms of neurodegeneration in Alzheimer's disease |journal=Hum. Mol. Genet. |volume=19 |issue=R1 |pages=R12–20 |year=2010 |pmid=20413653 |pmc=2875049 |doi=10.1093/hmg/ddq160 |url=}}</ref>
The [[pathogenesis]] of Alzheimer's dementia (AD) can be explained by four [[pathological]] processes. The processes involved in the development of AD and their [[molecular]] basis is as follows:<ref name="pmid20413653">{{cite journal |vauthors=Crews L, Masliah E |title=Molecular mechanisms of neurodegeneration in Alzheimer's disease |journal=Hum. Mol. Genet. |volume=19 |issue=R1 |pages=R12–20 |year=2010 |pmid=20413653 |pmc=2875049 |doi=10.1093/hmg/ddq160 |url=}}</ref><ref name="pmid30135715">{{cite journal |vauthors=Weller J, Budson A |title=Current understanding of Alzheimer's disease diagnosis and treatment |journal=F1000Res |volume=7 |issue= |pages= |date=2018 |pmid=30135715 |pmc=6073093 |doi=10.12688/f1000research.14506.1 |url=}}</ref>
=== (i) [[Neuronal]] loss ===
=== (i) [[Neuronal]] loss ===
*[[Neurogenesis]] is a complex process characterized by several progressive steps, including [[neural]] progenitor cell (NPC) [[proliferation]], migration, [[differentiation]] ([[cell]] fate commitment) and [[maturation]], including growth and [[synapse]] formation
*[[Neurogenesis]] is a complex process characterized by several progressive steps, including [[neural]] progenitor cell (NPC) [[proliferation]], migration, [[differentiation]] ([[cell]] fate commitment) and [[maturation]], including growth and [[synapse]] formation
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*In response to Aβ, [[Tau protein|tau]] is relocated from [[axons]] and [[dendrites]] into the somatodendritic compartment<ref name="pmid2117840">{{cite journal |vauthors=Delacourte A, Flament S, Dibe EM, Hublau P, Sablonnière B, Hémon B, Shérrer V, Défossez A |title=Pathological proteins Tau 64 and 69 are specifically expressed in the somatodendritic domain of the degenerating cortical neurons during Alzheimer's disease. Demonstration with a panel of antibodies against Tau proteins |journal=Acta Neuropathol. |volume=80 |issue=2 |pages=111–7 |year=1990 |pmid=2117840 |doi= |url=}}</ref>
*In response to Aβ, [[Tau protein|tau]] is relocated from [[axons]] and [[dendrites]] into the somatodendritic compartment<ref name="pmid2117840">{{cite journal |vauthors=Delacourte A, Flament S, Dibe EM, Hublau P, Sablonnière B, Hémon B, Shérrer V, Défossez A |title=Pathological proteins Tau 64 and 69 are specifically expressed in the somatodendritic domain of the degenerating cortical neurons during Alzheimer's disease. Demonstration with a panel of antibodies against Tau proteins |journal=Acta Neuropathol. |volume=80 |issue=2 |pages=111–7 |year=1990 |pmid=2117840 |doi= |url=}}</ref>
*Excess [[Fyn (biochemistry)|fyn]] accompanies the excess [[Tau protein|tau]] in AD [[dendrites]] and upregulates [[NMDA receptor]] activity in those areas, causing an increased [[calcium]] influx. This [[calcium]]-driven [[excitotoxicity]] can damage [[postsynaptic]] sites and cause [[neurodegeneration]]
*Excess [[Fyn (biochemistry)|fyn]] accompanies the excess [[Tau protein|tau]] in AD [[dendrites]] and upregulates [[NMDA receptor]] activity in those areas, causing an increased [[calcium]] influx. This [[calcium]]-driven [[excitotoxicity]] can damage [[postsynaptic]] sites and cause [[neurodegeneration]]
== Genetics ==
== Genetics ==
[[Genetic]] origin of Alzheimer's dementia  (AD) demonstrates an [[autosomal dominant]] pattern of [[Inheritance (genetic algorithm)|inheritance]]. Alzheimer's dementia arising from [[genetic]] alterations may lead to early onset (<60 years) of disease. The following mutations are implicated in the development of AD are:<ref name="urlAlzheimer Disease Overview - GeneReviews® - NCBI Bookshelf">{{cite web |url=https://www.ncbi.nlm.nih.gov/books/NBK1161/ |title=Alzheimer Disease Overview - GeneReviews® - NCBI Bookshelf |format= |work= |accessdate=}}</ref><div style="-webkit-user-select: none;">
[[Genetic]] origin of Alzheimer's dementia  (AD) demonstrates an [[autosomal dominant]] pattern of [[Inheritance (genetic algorithm)|inheritance]]. Alzheimer's dementia arising from [[genetic]] alterations may lead to early onset (<60 years) of disease. The following mutations are implicated in the development of AD are:<ref name="urlAlzheimer Disease Overview - GeneReviews® - NCBI Bookshelf">{{cite web |url=https://www.ncbi.nlm.nih.gov/books/NBK1161/ |title=Alzheimer Disease Overview - GeneReviews® - NCBI Bookshelf |format= |work= |accessdate=}}</ref><div style="-webkit-user-select: none;">

Revision as of 07:15, 19 May 2020

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Syed Hassan A. Kazmi BSc, MD [2], Aravind Reddy Kothagadi M.B.B.S[3]

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Overview

Alzheimer disease (AD), is a progressive neurodegenerative disorder. The dysfunction of amyloid precursor protien (APP) metabolism and the resulting build up of of Aβ peptides and their aggregation in the form of senile plaques in the brain parenchyma of individuals have been considered pivotal for neurodegeneration in the disease. Cognitive impairment in patients with AD is closely associated with synaptic loss in the neocortex and limbic system. In familial forms of AD, mutations result in an increased Aβ production or aggregation, in sporadic AD, failure of the clearance mechanisms might play a key role. Loss of mature neurons and alterations in neural progenitor cells (NPCs) in areas such as the dentate gyrus (DG) of the hippocampus have been found to be responsible for manifestations of AD. On gross pathology, temporal atrophy (hippocampus in particular), dilation of lateral ventricles and third ventricle are characteristic findings of Alzheimer's disease. The microscopic histopathological features of alzheimer's disease consist neurofibrillary tangles, senile plaques, neuronal loss, and with or without cerebral amyloid angiopathy.

Pathophysiology

Alzheimer disease (AD), is a progressive neurodegenerative disorder. The dysfunction of amyloid precursor protien (APP) metabolism and the resulting build up of of Aβ peptides and their aggregation in the form of senile plaques in the brain parenchyma of individuals have been considered pivotal for neurodegeneration in the disease. There is also an accumulation of intracellular neurofibrillary tangles that consist of hyperphosphorylated tau protein and a profound loss of basal forebrain cholinergic neurons that innervate the hippocampus, and the neocortex.

Triggers

The following factors lead to the development of Alzheimer's dementia:

Pathogenesis

The pathogenesis of Alzheimer's dementia (AD) can be explained by four pathological processes. The processes involved in the development of AD and their molecular basis is as follows:[1][2]

(i) Neuronal loss

(ii) Aggregation of extra-cellular amyloid β (Aβ)

Constitutive (nonamyloidogenic) pathway

  • In the constitutive pathway, proteolysis of APP by α- and γ-secretases results in nonpathogenic fragments (sAPPα and α-C-terminal fragment)

Amyloidogenic pathway

(iii) CDK5 pathway

(iv) Formation of intraneuronal neurofibrillary tangles (tau protein accumulation)

Genetics

Genetic origin of Alzheimer's dementia (AD) demonstrates an autosomal dominant pattern of inheritance. Alzheimer's dementia arising from genetic alterations may lead to early onset (<60 years) of disease. The following mutations are implicated in the development of AD are:[20]

Common genes

Early onset (Alzheimer's dementia-AD 1, 3 and 4)

30-50 percent of early-onset Alzheimer's dementia (AD) is associated with an autosomal dominant inheritance and consists of mutations in the following genes:[21][22]

Late onset (Alzheimer's dementia -AD2)

Less common genes

Less common genes associated with the development of AD are:


Associated Conditions

Gross Pathology

Comparison of alzheimer's disease brain, By derivative work: Garrondo,"Alzheimer's Disease Education and Referral Center, a service of the National Institute on Aging.", via Wikimedia Commons

Microscopic Pathology

Neurofibrillary tangles in the Hippocampus of an old person with Alzheimer's, https://creativecommons.org/licenses/by-sa/3.0/deed.en
Biopsy specimen displaying a neuritic plaque in a case of Alzheimers Disease, https://creativecommons.org/licenses/by-sa/3.0/deed.en
Neurofibrillary tangles in the Hippocampus of elderly with Alzheimer, https://creativecommons.org/licenses/by-sa/3.0/deed.en

References

  1. Crews L, Masliah E (2010). "Molecular mechanisms of neurodegeneration in Alzheimer's disease". Hum. Mol. Genet. 19 (R1): R12–20. doi:10.1093/hmg/ddq160. PMC 2875049. PMID 20413653.
  2. Weller J, Budson A (2018). "Current understanding of Alzheimer's disease diagnosis and treatment". F1000Res. 7. doi:10.12688/f1000research.14506.1. PMC 6073093. PMID 30135715.
  3. 3.0 3.1 Beach TG, Walker R, McGeer EG (1989). "Patterns of gliosis in Alzheimer's disease and aging cerebrum". Glia. 2 (6): 420–36. doi:10.1002/glia.440020605. PMID 2531723.
  4. DeKosky ST, Scheff SW (1990). "Synapse loss in frontal cortex biopsies in Alzheimer's disease: correlation with cognitive severity". Ann. Neurol. 27 (5): 457–64. doi:10.1002/ana.410270502. PMID 2360787.
  5. Terry RD, Masliah E, Salmon DP, Butters N, DeTeresa R, Hill R, Hansen LA, Katzman R (1991). "Physical basis of cognitive alterations in Alzheimer's disease: synapse loss is the major correlate of cognitive impairment". Ann. Neurol. 30 (4): 572–80. doi:10.1002/ana.410300410. PMID 1789684.
  6. Boekhoorn K, Joels M, Lucassen PJ (2006). "Increased proliferation reflects glial and vascular-associated changes, but not neurogenesis in the presenile Alzheimer hippocampus". Neurobiol. Dis. 24 (1): 1–14. doi:10.1016/j.nbd.2006.04.017. PMID 16814555.
  7. Selkoe DJ (1989). "Amyloid beta protein precursor and the pathogenesis of Alzheimer's disease". Cell. 58 (4): 611–2. PMID 2504495.
  8. Tanzi RE, Gusella JF, Watkins PC, Bruns GA, St George-Hyslop P, Van Keuren ML, Patterson D, Pagan S, Kurnit DM, Neve RL (1987). "Amyloid beta protein gene: cDNA, mRNA distribution, and genetic linkage near the Alzheimer locus". Science. 235 (4791): 880–4. PMID 2949367.
  9. 9.0 9.1 Walsh DM, Selkoe DJ (2004). "Oligomers on the brain: the emerging role of soluble protein aggregates in neurodegeneration". Protein Pept. Lett. 11 (3): 213–28. PMID 15182223.
  10. Van Cauwenberghe C, Van Broeckhoven C, Sleegers K (2016). "The genetic landscape of Alzheimer disease: clinical implications and perspectives". Genet. Med. 18 (5): 421–30. doi:10.1038/gim.2015.117. PMC 4857183. PMID 26312828.
  11. Bendiske J, Bahr BA (2003). "Lysosomal activation is a compensatory response against protein accumulation and associated synaptopathogenesis--an approach for slowing Alzheimer disease?". J. Neuropathol. Exp. Neurol. 62 (5): 451–63. PMID 12769185.
  12. Volles MJ, Lansbury PT (2002). "Vesicle permeabilization by protofibrillar alpha-synuclein is sensitive to Parkinson's disease-linked mutations and occurs by a pore-like mechanism". Biochemistry. 41 (14): 4595–602. PMID 11926821.
  13. Selkoe DJ (1999). "Translating cell biology into therapeutic advances in Alzheimer's disease". Nature. 399 (6738 Suppl): A23–31. PMID 10392577.
  14. Lin H, Bhatia R, Lal R (2001). "Amyloid beta protein forms ion channels: implications for Alzheimer's disease pathophysiology". FASEB J. 15 (13): 2433–44. doi:10.1096/fj.01-0377com. PMID 11689468.
  15. Nakamura T, Lipton SA (2010). "Redox regulation of mitochondrial fission, protein misfolding, synaptic damage, and neuronal cell death: potential implications for Alzheimer's and Parkinson's diseases". Apoptosis. 15 (11): 1354–63. doi:10.1007/s10495-010-0476-x. PMC 2978885. PMID 20177970.
  16. Nixon RA, Cataldo AM (2006). "Lysosomal system pathways: genes to neurodegeneration in Alzheimer's disease". J. Alzheimers Dis. 9 (3 Suppl): 277–89. PMID 16914867.
  17. Matsubara M, Kusubata M, Ishiguro K, Uchida T, Titani K, Taniguchi H (1996). "Site-specific phosphorylation of synapsin I by mitogen-activated protein kinase and Cdk5 and its effects on physiological functions". J. Biol. Chem. 271 (35): 21108–13. PMID 8702879.
  18. Ittner LM, Ke YD, Delerue F, Bi M, Gladbach A, van Eersel J, Wölfing H, Chieng BC, Christie MJ, Napier IA, Eckert A, Staufenbiel M, Hardeman E, Götz J (2010). "Dendritic function of tau mediates amyloid-beta toxicity in Alzheimer's disease mouse models". Cell. 142 (3): 387–97. doi:10.1016/j.cell.2010.06.036. PMID 20655099.
  19. Delacourte A, Flament S, Dibe EM, Hublau P, Sablonnière B, Hémon B, Shérrer V, Défossez A (1990). "Pathological proteins Tau 64 and 69 are specifically expressed in the somatodendritic domain of the degenerating cortical neurons during Alzheimer's disease. Demonstration with a panel of antibodies against Tau proteins". Acta Neuropathol. 80 (2): 111–7. PMID 2117840.
  20. "Alzheimer Disease Overview - GeneReviews® - NCBI Bookshelf".
  21. Campion D, Dumanchin C, Hannequin D, Dubois B, Belliard S, Puel M, Thomas-Anterion C, Michon A, Martin C, Charbonnier F, Raux G, Camuzat A, Penet C, Mesnage V, Martinez M, Clerget-Darpoux F, Brice A, Frebourg T (1999). "Early-onset autosomal dominant Alzheimer disease: prevalence, genetic heterogeneity, and mutation spectrum". Am. J. Hum. Genet. 65 (3): 664–70. doi:10.1086/302553. PMC 1377972. PMID 10441572.
  22. Tsuang D, Larson EB, Bowen J, McCormick W, Teri L, Nochlin D, Leverenz JB, Peskind ER, Lim A, Raskind MA, Thompson ML, Mirra SS, Gearing M, Schellenberg GD, Kukull W (1999). "The utility of apolipoprotein E genotyping in the diagnosis of Alzheimer disease in a community-based case series". Arch. Neurol. 56 (12): 1489–95. PMID 10593304.
  23. Khachaturian AS, Corcoran CD, Mayer LS, Zandi PP, Breitner JC (2004). "Apolipoprotein E epsilon4 count affects age at onset of Alzheimer disease, but not lifetime susceptibility: The Cache County Study". Arch. Gen. Psychiatry. 61 (5): 518–24. doi:10.1001/archpsyc.61.5.518. PMID 15123497.
  24. Jonsson T, Stefansson H, Steinberg S, Jonsdottir I, Jonsson PV, Snaedal J, Bjornsson S, Huttenlocher J, Levey AI, Lah JJ, Rujescu D, Hampel H, Giegling I, Andreassen OA, Engedal K, Ulstein I, Djurovic S, Ibrahim-Verbaas C, Hofman A, Ikram MA, van Duijn CM, Thorsteinsdottir U, Kong A, Stefansson K (2013). "Variant of TREM2 associated with the risk of Alzheimer's disease". N. Engl. J. Med. 368 (2): 107–16. doi:10.1056/NEJMoa1211103. PMC 3677583. PMID 23150908.

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