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[PL2‐02]: Soluble Abeta oligomers (ADDLs) in Alzheimer's disease memory loss, therapeutics, and diagnostics
Author(s) -
Klein William
Publication year - 2005
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2005.06.317
Subject(s) - neuroscience , synapse , senile plaques , amyloid (mycology) , mechanism (biology) , synaptic plasticity , programmed cell death , cognitive decline , alzheimer's disease , dendritic spine , biology , disease , dementia , medicine , pathology , receptor , biochemistry , apoptosis , philosophy , hippocampal formation , epistemology
AD relative to apoE3. ApoE is a 299 amino acid protein that is the most abundant apolipoprotein in the central nervous system (CNS). In the CNS, it is primarily synthesized by glial cells and secreted in high density lipoprotein (HDL) like particles that contain cholesterol and phospholipids. Objective(s): While the mechanism(s) underlying apoE’s involvement in AD and CAA pathogenesis remains unknown, abundant evidence suggests that a major mechanism is via apoE’s ability to act as a chaperone for the amyloid(A ) peptide to modulate its clearance as well as the likelihood that it will aggregate in the brain. Our objective has been to understand at an anatomic, cellular, and molecular level how interactions between apoE and A predispose to AD and CAA as this may lead to novel diagnostic and treatment strategies. Methods: Using animal models that develop AD-like pathology as well as CAA, we have found that apoE appears to be involved in clearance of soluble forms of A in the brain. In addition, apoE isoforms influence the development of A -containing plaques in brain parenchyma and CAA with the order of the effect being E4E3E2. Evidence suggests that increased expression of apoE2 and apoE3 decrease the amount of A deposition. Understanding molecules and pathways that control the levels and expression of apoE may be novel targets for therapy. We have found that the protein ABCA1 is important for the normal production and levels of plasma HDL and is also critical for maintaining normal levels of apoE and apoE-associated cholesterol in the brain. Conclusions: Determining methods to alter expression or function of ABCA1 and/or other proteins that regulate apoE levels and its state of lipidation may be important future therapeutic targets to prevent, delay, and treat AD and CAA.