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F5‐02‐03: Targeting Aβ oligomer formation in Alzheimer's disease: Challenges and alternatives to oligomer‐specific therapeutic avenues
Author(s) -
Ryan Timothy M.,
Roberts Blaine R.,
McColl Gawain,
Hare Dominic J.,
Hinds Mark G.,
Barnham Kevin J.,
Curtain Cyril C.,
Masters Colin L.
Publication year - 2015
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.2015.07.429
Subject(s) - oligomer , chemistry , small molecule , neurotoxicity , neurodegeneration , in vivo , computational biology , biophysics , disease , neuroscience , biochemistry , biology , medicine , toxicity , pathology , microbiology and biotechnology , organic chemistry
Background: Alzheimer’s disease is characterized by Amyloid-ß (Aß) accumulation, with soluble oligomers (Aßo) being the most synaptotoxic. We sought to determine which Aß species correlated closely with disease progression. Once formed, Aßo acts to impair synpases through PrPand mGluR5 to activate the Fyn tyrosine kinase, a Src-related enzyme. We sought to repurpose a Src family kinase inhibitor oncology compound for AD. Methods:We characterized multiple Aß forms throughout the lifespan of various Alzheimer model mice, and in post-mortem human brain by specific binding assays and size exclusion chromatography. Inhibition of Aßo signaling to Fyn, Pyk2 and Glu receptors by a Fyn kinase inhibitor was tested in brain slice assays. After Fyn kinase inhibitor or vehicle treatment of wild type and AD transgenic mice, memory was assessed by Morris water maze and novel object recognition. For these cohorts, APP metabolism, synaptic markers (SV2 and PSD-95), and targets of Fyn (Pyk2 and Tau) were studied by immunohistochemistry and by immunoblotting. Results: Aß exists in several populations, where PrP-interacting oligomers are a high molecular weight Aß assembly present in multiple transgenic mice and human Alzheimer brain extract. Levels of PrP-interacting Aßomatch closely withmousememory impairment. Fyn kinase inhibitor treatment potently inhibits both Aßo-induced signaling and downstream phosphorylation of the AD risk gene product, Pyk2, and of NR2B Glu receptors in brain slices. After 4 weeks of treatment, Fyn kinase inhibitor dosing of APP/PS1 transgenic mice fully rescues spatial memory deficits and synaptic depletion, without altering APP or Aß metabolism. Conclusions: PrP-interacting Aßo species are high molecular weight from mouse and human brain and closely correlated with disease. Fyn inhibition reverses the effects of Aßo through the PrP–mGluR5 complex at the synapse, and rescues transgenic mouse models of AD.