In vivo testing of structure-based vaccine candidates targeting alzheimer's disease - protein misfolding is a significant contributor of neurodegenerative diseases, leading to pathological aggregation…

This Project Grant award from the National Institute on Aging (CFDA 93.866 - Aging Research) provides $356,174 to The Regents of the University of California, San Francisco (UCSF) to conduct in vivo testing of structure-based vaccine candidates targeting Alzheimer's disease. The goal is to determine the efficacy of an active immunization strategy in preserving cognitive and neural function by slowing the formation of amyloid-beta or tau protein aggregation in the brain. The research will use 5XFAD and hTau mouse models to evaluate the vaccine constructs through behavioral tests, electrophysiological recordings, and analysis of brain pathology. The award period is from December 1, 2024 to November 30, 2026.

In vivo testing of structure-based vaccine candidates targeting alzheimer's disease - protein misfolding is a significant contributor of neurodegenerative diseases, leading to pathological aggregation and potential gain of toxic function. Thus, strategies targeting the clearance of misfolded proteins such as a-beta and TAU have shown promise in reducing or slowing of the amyloid deposition including immunotherapies. Passive immunization with antibodies against aggregated a-beta are not only costly but also with limited efficacy in maintaining cognitive function and fit for only a small pool of eligible patients. Active immunization with engineered constructs using HET-S as a scaffold while carrying key conformational epitopes present on the surface of alpha-synuclein fibrils has significantly prolonged the survival of mice with parkinson's disease. Anti-sera from mice immunized with constructs made of HET-S and key structural residues from paired-helical filaments (TAU) and AΒ fibrils are immunoreactive to brain homogenates from both sporadic and familial forms of human alzheimer's disease patients. The goal of this study is to determine the efficacy of our active immunization strategy in prophylactically preserving cognitive and neural function by slowing the formation of a-beta amyloid or paired-helical filaments in the brain. To that end, 5XFAD mice will be immunized with a quadrivalent vaccine composed of 4 top performed constructs targeting AΒ during adolescence, and tested for memory function by Y-maze, novel object recognition and barnes maze tests at nine months of age, followed by in vivo extracellular recording using multichannel electrodes spanning the cortex and the hippocampus. Similarly, htau mice will be immunized with our top vaccine construct targeting TAU and subjected to the same battery of behavioral tests and electrophysiological recording. Brains will be examined for the amount of amyloid deposits and hyperphosphorylated TAU, respectively. Perl's stain will be used to detect potential side effect of microhemorrhage known to human ad patients receiving immunotherapy. Using in vitro and in vivo assays we will also determine whether the designed vaccine constructs activate the complement system, as this information can be used for further refinement of the vaccines to enhance the efficacy of the immune response for robust clearing of misfolded proteins and preventing cognitive decline.