By: Carolyn L. Crankshaw, BioFiles v7 n2, 2011, 4–8
BioFiles Volume 7, Number 2 — Neurodegenerative Diseases
Alzheimer's disease (AD) is the most common cause of dementia in the elderly and is characterized by gradual loss of cognitive functions. Hallmark pathohistological findings of AD include widespread neuronal degeneration, extracellular amyloid plaques and intracellular neurofibrillary tangles (NFT). Biochemical changes affecting multiple pathways contribute to AD pathology. Hyperphosphorylation of Tau (MAPT) causes aggregation, contributing to the formation of NFT. The protein product of DOCK3 stimulates Tau phosphorylation and also interacts with presenilin proteins, components of the γ-secretase complex involved in processing of the amyloid β precursor protein (APP). Genetic and biochemical data support the hypothesis that amyloid-β (Aβ) accumulation and aggregation in the brain contribute to the pathogenesis of AD. Aβ is derived from sequential proteolytic processing of APP by β-secretases (BACE1, BACE2) and the γ-secretase complex (APH1, NCSTN, PSEN1, PSEN2, PSENEN). The longer Aβ42 form has a higher tendency to aggregate and is more toxic than the shorter Aβ40 form. A common feature of most Familial Alzheimer's Disease (FAD) mutations is an increase in the generation of Aβ peptides, particularly Aβ42. Mutations associated with early-onset FAD are found in the APP gene itself or in the presenilin-1 (PSEN1) and presenilin-2 (PSEN2) genes. Another gene associated with early-onset FAD, TMED10, encodes a protein which regulates γ-secretase activity. Ubiquilin, a ubiquitin-like protein, interacts with presenilin-2 and is believed to promote presenilin protein accumulation.
FAD genetics and mouse models have shed light on early-onset AD pathogenesis, but the vast majority of AD cases occur late in life. The 4 allele of the apolipoprotein E (APOE) gene (ApoE e4 variant) is a major risk for late-onset AD (LOAD) compared to the APOE2 and APOE3 variants. ApoE mediates binding, internalization and catabolism of lipoprotein particles via interaction with members of the low density lipoprotein receptor (LDLR) family. The prototype of this family, LDLR, has a major role maintaining cholesterol homeostasis. ApoE receptors include LDLR, LDL receptor related proteins (LRP1, LRP1B, LRP2), apoE receptor 2 (ApoER2) and the very low density lipoprotein receptor (VLDLR). The basic functions of apoE in normal brain and the role of apoE in neurodegenerative disease remain unknown. It is thought the full length and soluble forms of the apoE receptors alter APP processing and Aβ clearance, thus contributing to AD pathogenesis. Seladin-1 (DHCR24), a crucial enzyme involved in sterol synthesis, is downregulated in regions of the brain affected by AD.
Another focus in AD research centers around inflammation. Patients who have succumbed to Alzheimer's show overexpression of interleukin-1 (IL1A) and the soluble astrocyte inflammatory cytokine S100B. Further, IL1 induces Tau expression and phosphorylation in rat brain, and staining brain sections from Alzheimer's patients reveals abundant MAPK1 in the same regions as hyperphosphorylated Tau. The contribution of these and other events to the pathophysiology and progression of AD continues to be actively investigated.
- Griffin, W.S.T. Inflammation and neurodegenerative disease. Am. J. Clin. Nutr. 2006, 83, 472S-474S.
- Li , Y., et al. Interleukin-1 mediates pathological effects of microglia on tau phosphrylation and on synaptophysin synthesis in cortical neurons through a p38-MAPK pathway. J. Neurosci. 2003, 23, 1605-11.
- Griffin, W.S.T. et al. Interleukin-1 mediates Alzheimer and Lewy body pathologies. J. Neuroinflammation. 2006, 3, 5.
- Goldgaber, D. et al. Characterization and chromosomal localization of a cDNA encoding brain amyloid of Alzheimer's disease. Science. 1987, 235, 877-880.
- Kang, J., et al. The precursor of Alzheimer's disease amyloid A4 protein resembles a cell surface receptor. Nature. 1987, 325, 733-736.
- Tanzi, R., et al. Amyloid beta protein gene: cDNA, mRNA distribution, and genetic linkage near the Alzheimer locus. Science. 1987, 235, 880-884.
- Tanaka, S., et al. Tissue-specific expression of three types of beta-protein precursor mRNA: enhancement of protease inhibitor-harboring types in Alzheimer's disease brain. Biochem. Biophys. Res. Commun. 1989, 165, 1406-1414.
- Haass, C., and Selkoe, D.J. Cellular processing of beta-amyloid precursor protein and the genesis of amyloid beta-peptide. Cell. 1993, 75, 1039-1042.
- Vassar, R. Beta-secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE. Science. 1999, 286, 735-741.
- Yan, R., et al. Membrane-anchored aspartyl protease with Alzheimer's disease beta-secretase activity. Nature. 1999, 402, 533-537.
- Sinha, S., et al. Purification and cloning of amyloid precursor protein beta-secretase from human brain. Nature. 1999, 402, 537-540.
- Price, D.L., and Sisodia, S.S. Mutant genes in familial Alzheimer's disease and transgenic models. Ann. Rev. Neurosci. 1998, 21, 479-505.
- Tanzi, R.E., et al. The Presenilin genes and their role in early-onset familial Alzheimer's disease. Alzheimer's Disease Rev. 1996, 1, 91-98.
- Schellenberg, G.D., et al. Genetic linkage evidence for a familial Alzheimer's disease locus on chromosome 14. Science. 1992, 258, 668-671.
- Maroteaux, L., and Scheller, R.H. The rat brain synucleins; family of proteins transiently associated with neuronal membrane. Mol. Brain. Res. 1991, 11, 335-343.
- Ueda, K., et al. Molecular cloning of cDNA encoding an unrecognized component of amyloid in Alzheimer disease. Proc. Natl. Acad. Sci. USA. 1993, 90, 11282-11286.
- Yu, G., et al. Nicastrin modulates presenilin-mediated notch/glp-1 signal transduction and betaAPP processing. Nature. 2000, 407, 48-54.
- Schenk, D., et al. Alzheimer's disease. A partner for presenilin. Nature. 2000, 407, 34-35.
- Sisodia, S.S. Neuroscience. An accomplice for gammasecretase brought into focus. Science. 2000, 289, 2296-2297.
- Usdin, T.B. et al. Molecular biology of the vesicular ACh transporter. Trends Neurosci. 1995, 18, 218-224.
- Varoqui, H., and Erickson, J.D. The cytoplasmic tail of the vesicular acetylcholine transporter contains a synaptic vesicle targeting signal. J. Biol. Chem. 1998, 273, 9094-9098.