Alzheimer's Disease


Alzheimer's Disease (AD) is a neurodegenerative disease of the central nervous system associated with progressive memory loss resulting in dementia. Two pathological characteristics are observed in AD patients at autopsy: extracellular plaques and intracellular tangles in the hippocampus, cerebral cortex, and other areas of the brain essential for cognitive function. Plaques are formed mostly from the deposition of amyloid ß (Aß), a peptide derived from amyloid precursor protein (APP). Filamentous tangles are formed from paired helical filaments composed of neurofilament and hyperphosphorylated tau protein, a microtubule-associated protein. It is not clear, however, whether these two pathological changes are the markers or the causes of AD. Late-onset/sporadic AD has virtually identical pathology to early-onset/familial AD (FAD), thus suggesting common pathogenic pathways for both forms of AD. All mutations associated with APP and PS proteins can lead to an increase in the production of Aß peptides, specifically the more amyloidogenic form, Aß42. In addition to genetic influences on amyloid plaque and intracellular tangle formation, environmental factors (e.g., cytokines, neurotoxins, etc.) may also play important roles in the development and progression of AD.


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Amyloid Precusor Protein (APP)

APP is an integral membrane protein, occurring in different isoforms. The common isoforms contain 695 (APP695), 751 (APP751) and 771 (APP771) amino acids (aa), respectively. Among these isoforms, APP695 is the major isoform and is expressed exclusively in neurons. In contrast, APP751 and APP770 are expressed in both neural and non-neural cells. The primary structure of APP has a signal sequence, a large extramembranous N-terminal region, a single transmembrane domain, and a small 47 aa residue cytoplasmic C-terminal tail. The APP proteins mature in the endoplasmic reticulum and Golgi apparatus and exhibit post-translational modifications, including phosphorylation, glycosylation and sulfation. Proteolytic cleavage of APP results in generation of Aß peptides of various lengths. In the brains of AD patients, formation of insoluble, fibrillar plaques is facilitated by an increase and accumulation of Aß peptides. The predominant form of Aß peptides found within conditioned cell culture media and cerebrospinal fluid is the shorter Aß40 peptide. Aß42, however, is the Aß peptide form initially deposited within the extracellular plaques of AD patients. All FAD-linked mutations identified within APP lead to the increased production of Aß42. Additionally, Aß42 tends to aggregate at a faster rate and at lower concentrations than the Aß40 form. Three proteases, a-, ß- and -secretases, are involved in APP cleavage. At the cell surface, APP undergoes proteolysis by a α-secretase that cleaves between Lys687 and Leu688 thus releasing a large, soluble ectodomain (α-APP). The C-terminal fragment (83 aa, ~10 kDa) is retained within the cell membrane. This fragment can then be cleaved by -secretase at aa residues 711 or 713 within the APP transmembrane domain thereby releasing the p3 peptide. Alternatively, uncleaved cell surface APP can be internalized by endocytosis via coated vesicles in the distal cytoplasmic domain. The full-length APP can then be trafficked to later endosomes and lysosomes for degradation or transferred to early endosomes for generation of Aß peptides. In the early endosomes, APP is cleaved by ß-secretase after Met671, creating a membrane-retained C-terminal fragment (99 aa, ~12 kDa). Cleavage by ß-secretase exhibits relatively rigid primary aa sequence requirements (i.e., between Met671 and Asp672 of APP). At the membrane surface, the 12 kDa C-terminal fragment can then be further cleaved by secretase within the hydrophobic transmembrane domain at either Val711 or Ile713 thus releasing an Aß peptide (i.e., either Aß40 and Aß42). Identification and characterization of the ß- and -secretases have been important areas of focus in AD research. Although several candidates have been suggested for ß-secretase, BACE is the only one identified having complete ß-secretase activity. Cloning and expression of the enzyme reveals that the human brain ß-secretase/BACE is a membrane-bound aspartic proteinase. The -secretase has not been definitively identified yet. Numerous studies, however, have linked -secretase and PS1 as either the same enzyme molecule or cofactors within the same complex.