Alzheimer's disease (AD) is a progressive neurodegenerative and ultimately fatal dementia. Synaptic loss has been demonstrated to be the anatomic substrate underlying the onset of dementia in patients. However, the pathological mechanism of synapse loss remains elusive. The burden of oligomers of ?-amyloid (A?) is a strong inverse correlate of synapse loss in AD patients. AD extract containing natural oligomers typically attack post synapse and the AD extract induces amyloidogenesis in animals. Oligomers of A? target Shank protein, which is an organizer of glutamate receptors in post synapse, was shown to be involved in pathological change in AD. Based on these findings, we hypothesize that human natural pathogenic oligomers of A? trigger catastrophic accumulation of toxic oligomers, and destruct synaptic integrity between Shank proteins and glutamate receptors underlying synapse loss in AD. Needs addressed by this proposal: A major concern is whether the natural dodecamers of A? (12-mer) from human AD brain induce oligomer accumulation and amyloidogenesis in vivo/vitro, and destroy synaptic function.
AIM 1 : Test the hypothesis that pathological 12-mer triggers catastrophic accumulation of toxic 12-mer in vivo and in vitro.
AIM 2 : Test the prediction that oligomers of A? trigger Shank-postsynaptic platform collapse resulting in loss of synaptic structure and function. To characterize human oligomers of A?, we have developed methods to isolate oligomers of A? from human AD brain under native conditions. The proposed experiments will explore a new biological activity of natural oligomers from AD brain tissue. If successful, this study will also identify new therapeutic targets which will open novel ways to neutralize this neurotoxin and protect synaptic function. ? ?
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