Duff, K. E. | Search bioRxiv

bioRxiv2018

Attenuation of Aβ-associated hyperactivity reduces Aβ and tau pathology along the entorhinal cortex-hippocampal network

High levels of the amyloid-beta (A{beta}) peptide have been shown to disrupt neuronal function and induce hyperexcitability but it is unclear what effects A{beta}-associated hyperexcitability may have on tauopathy pathogenesis or propagation in vivo. Using a novel transgenic mouse line to model the impact of hAPP/A{beta} accumulation on tauopathy in the entorhinal cortex-hippocampal (EC-HIPP) network, we demonstrate that hAPP aggravates EC tau aggregation and accelerates pathological tau spread into the hippocampus. In vivo recordings revealed a strong role for hAPP/A{beta}, but not tau, in the emergence of EC neuronal hyperactivity and impaired theta rhythmicity. Chemogenetic attenuation of A{beta}-associated hyperactivity led to reduced hAPP/A{beta} accumulation and reduction of pathological tau in downstream hippocampus. These data strongly support the hypothesis that in Alzheimers disease (AD), A{beta}-associated hyperactivity accelerates the progression of pathological tau along vulnerable neuronal circuits, and demonstrates the utility of chronic, neuromodulatory approaches in ameliorating AD pathology in vivo.

neuroscience↗

bioRxiv2018

APOE4 is Associated with Differential Regional Vulnerability to Bioenergetic Deficits in Aged APOE Mice

The {varepsilon}4 allele of apolipoprotein E (APOE) is the dominant genetic risk factor for late-onset Alzheimers disease (AD). However, the reason for the association between APOE4 and AD remains unclear. While much of the research has focused on the ability of the apoE4 protein to increase the aggregation and decrease the clearance of A{beta}, there is also an abundance of data showing that APOE4 negatively impacts many additional processes in the brain, including bioenergetics. In order to gain a more comprehensive understanding of the APOE4s role in AD pathogenesis, we performed a multi-omic analysis of APOE4 vs. APOE3 expression in the entorhinal cortex (EC) and primary visual cortex (PVC) of aged APOE mice. These studies revealed region-specific alterations in several bioenergetic pathways, including oxidative phosphorylation (OxPhos), the TCA-cycle and fatty acid metabolism. Follow-up analysis utilizing the Seahorse platform revealed decreased mitochondrial respiration in the hippocampus and cortex of aged APOE4 vs. APOE3 mice, but not in the EC of these mice. Additional studies, as well as the original multi-omic data suggest that bioernergetic pathways in the EC of aged APOE mice may be differentially regulated by APOE4 expression. Given the importance of the EC as one of the first regions to be affected by AD pathology in humans, this differential bionenergetic regulation observed in the EC vs. other brain regions of aged APOE4 mice may play an important role in the pathogenesis of AD, particularly among APOE4 carriers.

neuroscience↗