AAV-Enhancer-Driven Targeting of Layer 2/3 Entorhinal Neurons Selectively Vulnerable to Alzheimer’s Disease

Abstract

Alzheimer’s Disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline. Current therapeutics for AD only temporarily alleviate the symptoms of cognitive impairment, and broadly impact multiple brain regions without targeting localized cell populations that specifically drive AD pathology. Recent research suggests that the entorhinal cortex may be one of the first brain regions impacted by AD pathology. Layer 2 (L2) neurons within the entorhinal cortex are particularly vulnerable to neurodegeneration, as this layer exhibits the initial and most severe cellular degeneration of any other brain region in AD patients. This identifies these neurons as a reasonable target for studying AD pathology. This is a proof of principle study with the goal of identifying and validating glutamatergic L2/3 cell-type specific entorhinal cortex candidate enhancers. The study aims to address a knowledge gap in current AD research as there is currently a primary focus on Aβ accumulation and tau hyperphosphorylation as causal drivers of the disease pathology, even though dysfunction of the entorhinal cortex is one of the first signs of AD. Cell-type specific targeting of neurons in this region will provide a better understanding of the role of neural circuits containing L2 neurons, which are known to be particularly vulnerable to neurodegeneration. Successful identification and validation of a cell type-specific L2 entorhinal enhancer may lead to therapeutics aimed at preserving cognitive function using targeted adeno-associated virus (AAV) delivery.