Unraveling a Vicious Cycle: Entorhinal Cortex Hyperactivity, Neuroinflammation, and the Progression of Tauopathy

The entorhinal cortex (EC) is ground zero for Alzheimer’s disease (AD), showing early signs of tauopathy and neuroinflammation, which then spread through the entorhinal-hippocampal (EC-HPC) circuit. There are major gaps in knowledge regarding why the EC is vulnerable early in AD, and what drives disease progression from the EC to the HPC. We developed an approach to image EC layer 2 projection neuron activity in vivo with 2-photon microscopy in models of tauopathy. We discovered EC layer 2 projections are profoundly hyperactive. This is important because neural activity causes the release of toxic forms of tau and other disease associated proteins. Thus, hyperactivity in EC projection neurons may accelerate disease. In support of this, we found that directly inducing hyperactivity in EC projections (using chemogenetics) accelerates tauopathy spread to the HPC. It is essential to determine why EC layer 2 projections are hyperactive in tauopathy. It is well established that there is early neuroinflammation in the EC driven by microglial activation. In diseases such as epilepsy, activated microglia releases cytokines that cause neuronal hyperactivity. Thus, microglial activation may drive the hyperactivity we found in tauopathy. Our central hypotheses are 1) EC layer 2 hyperactivity drives disease progression through the EC-HPC circuit, and 2) Neuroinflammation within the EC drives neuronal hyperactivity in tauopathy. These hypotheses form the core of our model that three factors in the EC – tauopathy, neuroinflammation, and neuronal hyperactivity – form a vicious cycle that drives disease progression in the EC-HPC circuit. We will test this model in three synergistic, but independent, aims utilizing innovative in vivo 2-photon microscopy and targeted neuronal manipulation. In Aim 1, we will determine the longitudinal progression of neuronal hyperactivity and neuroinflammation in the EC-HPC circuit in two models of tauopathy. In Aim 2, we will test the causal role of EC layer 2 projection hyperactivity in disease progression in tauopathy. To do so, we will selectivity suppress activity in EC layer 2 projection neurons using chemogenetics. In Aim 3, we will test the causal role of neuroinflammation in EC-HPC circuit hyperactivity in tauopathy. Altogether, our innovative aims will fill major gaps in knowledge regarding the roles of EC layer 2 projection neurons, neuronal hyperactivity, and neuroinflammation in the progression of tauopathy in the EC-HPC circuit. Project Number: 1R01AG086475-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Institute on Aging (NIA) | Principal Investigator: Jae-eun Miller | Institution: COLUMBIA UNIVERSITY HEALTH SCIENCES, NEW YORK, NY | Award Amount: $529,744 | Activity Code: R01 | Study Section: Special Emphasis Panel[ZRG1 AN-Q (55)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11296459