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Synaptic targeting by Aβ oligomers (ADDLS) as a basis for memory loss in early Alzheimer's disease
Author(s) -
Klein William L.
Publication year - 2006
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.2005.11.003
Subject(s) - neuroscience , long term potentiation , mechanism (biology) , synaptic plasticity , disease , amyloid (mycology) , synapse , metaplasticity , alzheimer's disease , biology , psychology , medicine , receptor , pathology , philosophy , biochemistry , botany , epistemology
Early diagnosis and treatment of Alzheimer's Disease (AD) ultimately will require identification of its pathogenic mechanism. Such a mechanism must explain the hallmark of early AD—a profound inability to form new memories. For many years, the most promising hypothesis maintained that memory failure derived from neuron death induced by insoluble deposits of amyloid fibrils. Newer findings, however, suggest that memory loss, especially in early AD, may be a failure in synaptic plasticity caused by small soluble Aβ oligomers (“ADDLs”). ADDLs are neurologically potent toxins that rapidly inhibit long‐term potentiation and reversal of long‐term depression, classic paradigms for learning and memory. In human samples, ADDLs show striking increases in AD brain and CSF. The ADDL hypothesis is considerably reinforced by nerve cell biology studies showing that ADDLs specifically attack synapses, essentially acting as gain‐of‐function pathogenic ligands. Selective damage by ADDLs to memory‐linked synaptic mechanisms provides an appealing explanation for early AD memory loss and suggests that ADDLs provide a valid target for therapeutics and diagnostics.