TRANSCRIPTOMIC NEURONAL SUBTYPE-SPECIFIC RESPONSES TO TAU OVEREXPRESSION IN THE ENTORHINAL CORTEX POINT TO NEW PATHWAYS FOR UNDERSTANDING EARLY ALZHEIMER'S DISEASE PATHOGENESIS

Alzheimer’s Disease (AD) is characterized by two key pathological features: amyloid plaques and neurofibrillary tangles (NFTs). NFTs, intracellular aggregates of pathological species of microtubule-associated protein tau, are typically first seen in a specific subset of neurons (called “pre-alpha” neurons) in the superficial entorhinal cortex (EC), corresponding to Braak stage I, followed by spread throughout the entorhinal cortex (II), and then to synaptically connected regions such as the hippocampus (stage III), and eventually throughout the cortex (stages IV–V). However, why certain EC neurons develop NFTs earlier than others is poorly understood.
We therefore injected AAVs expressing wildtype human Tau (hTau) and GFP under the control of the human synapsin promoter in both wildtype and AD rats such that hTau was overexpressed in a variety of neuronal cell types in the entorhinal and surrounding cortices. We then followed the development of pathological tau species in different neuronal subtypes with both immunohistochemistry and snRNAseq. Immunohistochemistry showed different pathological tau species are generated at different rates in different neuronal subtypes. We found that, as expected, the presumed cognate neurons of human pre-alpha cells were highly prone to turning hTau into pathological tau species. Surprisingly, other entorhinal neurons were even more susceptible, especially with certain antigens. Transcriptomic analysis of the snRNAseq data corroborates this, with entorhinal neuronal subtypes showing the greatest response to hTau overexpression in terms of changes in gene expression. We present gene-network analyses providing mechanistic insight into the enhanced vulnerability of distinct entorhinal celltypes to the development of tauopathy.