Biological Amyloids in the Mammalian Brain Extracellular Matrix

PROJECT SUMMARY / ABSTRACT The brain extracellular matrix (ECM) plays critical roles in synaptic plasticity including experience/adaptive-based changes in brain function suggesting an inherent malleability in ECM structure. Although changes in ECM chondroitin sulfate proteoglycans (CSPGs) and proteases contribute to ECM remodeling, the underlying

mechanisms that enable ECM plasticity are still unknown. Our central hypothesis is that functional amyloids, including CRES (cystatin-related epididymal spermatogenic) subgroup members, and extracellular nucleic acids are critical elements of the brain ECM infrastructure that allow its adaptability, including sex-specific responses.

We hypothesize also that alterations or loss of these components change brain ECM structure resulting in altered functions that can lead to pathologies such as Alzheimer’s disease (AD). The objective of this R21 proposal is to: 1) establish that amyloids, including CRES, and extracellular nucleic acids are components of the mouse and

human brain ECM using amyloid-specific reagents and biochemical and biophysical approaches; and 2) determine the sex-specific contributions of CRES/CRES amyloid to ECM structure using a CRES KO mouse model. Collectively, our studies will identify entirely new structural elements in the brain ECM and suggest a

novel mechanism by which the brain ECM can remodel enabling plasticity and sex-specific responses.