Cellular Pathology and Biomarkers Following Gene Delivered Tauopathy in Aged Macaque Monkeys

About This Grant

Project Summary/Abstract Under the auspices of R24 grant AG073138 (in response to RFA-AG-21-003), we have developed a highly innovative model of Alzheimer’s disease (AD) and related dementias (ADRD) based on intracortical injections of an AAV carrying an aggregation-prone isoform of human tau containing two mutations (AAV-2xTau) into the entorhinal cortex (ERC) of adult macaques. During this funded application, we have comprehensively characterized this model at multiple levels of resolution across several time points (6 weeks, 3 months, and 6 months), including local patterns of tau biochemical progression (from normal tau to neurofibrillary tangle formation, including multiple hyperphosphorylated pre-tangle intermediate species). We identified a window of cell loss in the medial temporal lobe, with little to no cell loss up to 3 months, but extensive thioflavin S expression with neuronal loss by 6 months post-treatment, providing a known therapeutic window for future experiments. We associated these changes with markers of inflammation with microglial infiltration occurring early and astrogliosis occurring later in the preclinical disease process. Critically, we observed a time-dependent permissive templating of pathology across the ERC connectome, which by 6 months includes both hippocampal and neocortical propagation of misfolded proteins in a pattern resembling what is seen in AD. We have also seen changes in both CSF and blood biomarkers that identified tau isoforms, neurofilament light chain changes, inflammatory markers, as well as reductions in brain-derived neurotrophic factors just as seen in human AD. Finally, we observed widespread neuroimaging changes on MRI and PET changes following gene delivery of AAV-2xTau. The theme of this new application is to further assess gene delivery of AAV-2xTau but now in aged monkeys (>22 years old), which models individuals with AD and other tauopathies more accurately. Since the R24 grant is not renewable, we have been told by NIA leadership we should continue this program using an RO1 mechanism. We will compare the data collected in the aged monkeys to adult monkeys that were identically treated and from whom brain sections, as well as serum and CSF samples, remain available. Thus concomitant analyses from adult and aged animals can take place without confound. Additionally, we will assess AAV-double mutant tau treated adult and aged monkeys using powerful quantitative neuroanatomical techniques examining early cellular and synaptic events reflecting the initial progression of tau-based neuropathology, including cellular events reflecting disruption of the cytoskeleton, spine loss across the dendritic tree, and detailed analyses of affected synapses/connections.