The Secretory Chaperone 7B2 as an Endogenous Regulator of Amyloid Pathology

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DESCRIPTION (provided by applicant): Alzheimer's disease (AD) affects 5.2 million Americans over 65, a number expected to increase along with the general aging of the US population. While remarkable progress has been made in the last decade in defining the toxic effects of the amyloid species thought to be involved in loss of cognitive function, much remains to be learned regarding amyloid plaque pathogenesis. Recent data support the idea that chaperones, proteins which control folding homeostasis, contribute to proper neuronal function in a variety of ways. Our laboratory has recently shown that 7B2, a small secreted neuronal protein, is associated with brain amyloid plaques in tissues from both AD humans and from mouse AD models. These data are supported by five independent bioinformatics studies indicating that this protein represents a potential CSF biomarker for neurodegenerative disease. Although present in the secretory pathway and not the cytosol, 7B2 exhibits many biochemical characteristics similar to those of small heat shock protein chaperones. Like alpha crystallin, a member of the heat shock chaperone family, 7B2 can potently block the fibrillation of beta amyloid 1-42 in in vitro tests, and also blocks the cytotoxicity of beta amyloid added to Neuro 2A cell cultures. The current R21 proposal is to test the hypothesis that brain 7B2 levels can control the extent of amyloid plaque deposition and affect cognition in a known mouse model of Alzheimer's. We propose to cross existing mouse strains that either over- or underexpress 7B2 with the APP/PS1 Alzheimer's disease model mouse. Cognitive abilities will be assessed at 6 and 12 months of age in a Morris water maze. Plaque pathology will be quantitated in cortical and hippocampal slices in 6 animals of each genotype; 7B2 immunoreactivity will be measured in concert. Amyloid oligomerization state will be examined in brains of separate animals using chemical and centrifugal separation followed by ELISA and also correlated with genotype. Collectively, these experiments constitute a direct test of our hypothesis that 7B2 levels are negatively correlated with amyloid plaque and oligomer formation.