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Alzheimer's Disease |
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Alzheimer's disease (AD) is characterized by amyloid plaques and neurofibrillary tangles in the brain. Several molecules are involved in the disease:
Their causal relationships have been largely unveiled. It turns out that beta amyloid plays the central role in the development of Alzheimer's disease (more info). Beta amyloid is a protein fragment generated from a larger protein called amyloid precursor protein (APP) (more info). These fragments may clump together and mix with other molecules, neurons, and non-nerve cells to form the amyloid plaque. The length of an Ab peptide ranges from 39 to 43 amino acids. It has been found that the longer one is more likely to form plaques (thereby more toxic) than the shorter one.
Associated GenesFour genes have been conclusively shown to affect the development of Alzheimer's disease: the APP gene on chromosome 21, the PS1 gene on chromosome 14, the PS2 gene on chromosome 1, and the apoE gene on chromosome 19. Mutations of APP, PS1 and PS2 genes are linked to the rare early-onset form of familial AD. Many people with Down's syndrome also develop AD-like dementia by the age of 40. They have three copies of chromosome 21 (where the APP gene is located), instead of two for normal people. The APP gene encodes the precursor protein to beta amyloid. One more copy of the APP gene in people with Down's syndrome should make more precursor proteins, thereby producing more Ab peptides. Mutations of the APP gene in the early-onset AD either increase the total level of Ab or favor the production of longer (more toxic) Ab. Both cases increase the chance of forming amyloid plaques. PS1 and PS2 genes encode presenilin 1 and presenilin 2, respectively. They are the components of the g-secretase, which cleaves amyloid precursor protein (APP) to generate Ab. Their mutations favor the production of longer (more toxic) Ab. Apolipoprotein E (apoE) is a protein with 299 amino acids. Its gene is polymorphic, with three alleles, encoding three protein isoforms: apoE2, apoE3, and apoE4. Their frequencies in populations are 5–10%, 60–70%, and 15–20%, respectively. People with apoE4 are more likely to develop Alzheimer's disease. Experimentally, it has been found that apoE can bind to Ab, thereby inhibiting its clearance and stimulating its deposition. The apoE4 binds to Ab more rapidly than apoE3.
Review Articles: Alzheimer disease therapy: Can the amyloid cascade be halted? - J. Clin. Invest., 2003. Cholesterol, lipid rafts, and disease - J. Clin. Invest., 2002. Amyloid Precursor Protein, Presenilins, and a-Synuclein: Molecular Pathogenesis and Pharmacological Applications in Alzheimer's Disease - Pharmacological Review, 2002 The Role of Presenilins in g-Secretase Activity - J. Biol. Chem., 2001. Alzheimer's Disease: Genes, Proteins, and Therapy - Physiological Reviews, 2001.
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