Mapping and modeling inhibitory interneurons in Alzheimer's disease and related dementias: novel strategies to reverse neural network dysfunction

ABSTRACT Alzheimer’s disease (AD) and AD-related dementias (ADRD) are prevalent and costly, with no disease-modifying therapies. Emerging data demonstrate that disruptions within inhibitory interneurons contribute significantly to AD/ADRD pathophysiology. Interneurons normally regulate excitatory firing of neuronal networks, enabling the tuning and adaptability of circuits

which subserve functions such as memory and cognition. Altered interneuron inhibition is seen in brains of human AD/ADRD subjects, which leads to hyperexcitability, hypersynchrony, and epileptiform activity that impairs memory and cognition. Synaptic overactivity also increases amyloid beta (Aβ) levels, while enhancing interneuron inhibitory activity promotes Aβ clearance.

Yet, the upstream causes of interneuron dysfunction in AD/ADRD are unclear. There is a critical need to define mechanisms of interneuron pathology and the resultant hyperexcitability in AD/ADRD to develop effective therapies. This proposal will catalog mediators of interneuron dysfunction, and develop strategies to reverse this pathology. Our central hypothesis is that

abnormal mitochondrial function is a major and early contributor to interneuron dysfunction, and that transplantation of iPSC-derived interneuron precursors will restore cognitive and memory circuits. Our rationale is that, by defining faulty interneuron biology and connections, concrete therapeutic targets will be made feasible for AD/ADRD. We have three Aims. Aim 1 will identify

disrupted interneuron gene expression by studying interneurons within hippocampal and cortical subregions of human post-mortem AD brain. Using a spatial transcriptomic whole transcriptome approach, we will map aberrant interneuron genes and identify mechanistic targets for reversing hyperexcitability and restoring cognitive function. Aim 2 will define inhibitory dysfunction in vitro

by characterizing AD-derived induced interneurons using metabolic phenotyping, immunocytochemical staining, and Aβ toxicity assays. AD-derived interneurons will then be modified to express genes aimed at reversing abnormalities seen in prior studies with the goal of restoring interneuron regulatory physiology. This aim will determine whether corrected

interneurons represent a viable patient-specific therapeutic strategy. Aim 3 will transplant healthy induced interneurons into hippocampal structures of an AD mouse model, assessing graft survival and hippocampal-based memory performance. Here, we will determine the impact of interneuron augmentation on behavior and neurodegeneration in vivo, providing a rationale

for future cell-based therapies. Overall, understanding interneuron pathophysiology and its contribution to neural circuit dysregulation in AD/ADRD will help uncover innovative treatments for AD/ADRD and similar illnesses involving dysregulated neural networks.