Neurotoxicity of beta-Amyloid Protein: Oligomerization, Channel Formation, and Calcium Dyshomeostasis.
Summary of "Neurotoxicity of beta-Amyloid Protein: Oligomerization, Channel Formation, and Calcium Dyshomeostasis."
Numerous studies have indicated that Alzheimer's amyloid-beta protein (Abeta) causes the degeneration of synapses and neurons, finally inducing the pathogenesis of Alzheimer's disease (AD). Recent approaches have emphasized the importance of Abeta oligomerization which enhances its neurotoxicity and synaptotoxicity. Our work as well as other groups' research have demonstrated that Abeta oligomers are directly incorporated into neuronal membranes and form calcium-permeable ion channels (amyloid channels). Although the precise molecular mechanism of Abeta neurotoxicity remains elusive, the formation of amyloid channels and the resultant abnormal elevation of the intracellular calcium levels might be the primary event for neurodegeneration, considering that calcium dyshomeostasis triggers various apoptotic pathways. This article reviews the current understanding of AD pathology based on the hypothesis that the disruption of calcium homeostasis through amyloid channels may be the molecular basis of Abeta neurotoxicity. The potential development of preventive agents for new therapeutic targets is also discussed.
Department of Analytical Chemistry School of Pharmaceutical Sciences Kyushu University of Health and Welfare 1714-1 Yoshino-cho, Nobeoka-shi, Miyazaki 882-8508, Japan. firstname.lastname@example.org.
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Medical and Biotech [MESH] Definitions
Amyloid Beta-protein Precursor
A precursor to the AMYLOID BETA-PROTEIN (beta/A4). Alterations in the expression of the amyloid beta-protein precursor (ABPP) gene, located on chromosome 21, plays a role in the development of the neuropathology common to both ALZHEIMER DISEASE and DOWN SYNDROME. ABPP is associated with the extensive extracellular matrix secreted by neuronal cells. Upon cleavage, this precursor produces three proteins of varying amino acid lengths: 695, 751, and 770. The beta/A4 (695 amino acids) or beta-amyloid protein is the principal component of the extracellular amyloid in senile plaques found in ALZHEIMER DISEASE; DOWN SYNDROME and, to a limited extent, in normal aging.
A type of extracellularly deposited substance composed of an amyloid protein and additional components including HEPARAN SULFATE PROTEOGLYCAN; LAMININ; COLLAGEN TYPE IV; SERUM AMYLOID P-COMPONENT; and APOLIPOPROTEINS E which together form characteristic amyloid fibrils. The core of amyloid fibrils is formed by the stacking of overlapping beta-pleated sheet domains of the amyloid protein. There are many different amyloid proteins that have been found forming the core of the fibrils in vivo. However, amyloid can be formed from any protein that exposes beta-pleated strand conformations during unfolding or refolding. A common characteristic of amyloid is the ability to bind such dyes as CONGO RED and thioflavine.
Amyloid Precursor Protein Secretases
Endopeptidases that are specific for AMYLOID PROTEIN PRECURSOR. Three secretase subtypes referred to as alpha, beta, and gamma have been identified based upon the region of amyloid protein precursor they cleave.
A 4-kDa protein, 39-43 amino acids long, expressed by a gene located on chromosome 21. It is the major protein subunit of the vascular and plaque amyloid filaments in individuals with Alzheimer's disease and in aged individuals with trisomy 21 (DOWN SYNDROME). The protein is found predominantly in the nervous system, but there have been reports of its presence in non-neural tissue.
Peptides generated from AMYLOID BETA-PEPTIDES PRECURSOR. An amyloid fibrillar form of these peptides is the major component of amyloid plaques found in individuals with Alzheimer's disease and in aged individuals with trisomy 21 (DOWN SYNDROME). The peptide is found predominantly in the nervous system, but there have been reports of its presence in non-neural tissue.
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