Our Research

The neuropathological hallmarks of Alzheimer’s disease (AD) do not fully explain its clinical manifestations, particularly the progressive and severe decline in cognitive function. Our lab emphasizes the critical role of soluble, oligomeric forms of amyloid β-protein (oAβ42) in driving the selective dysfunction of neurons affected during the early stages of AD. We propose that elevated oAβ42 levels induce neuronal hyperexcitability by modulating specific ion channels expressed on these neurons. By uncovering these mechanisms, our work aims to (i) develop novel pharmacotherapies that target the root causes of neuronal dysfunction, rather than offering late-stage interventions with limited benefits and (ii) protect key neurons essential for memory and cognitive function in individuals with AD.

Neuronal functional stability relies on the brain's ability to maintain consistent, stable activity and information processing despite constant physical changes at the cellular level. It is governed by the precise regulation of ligand- and voltage-gated ion channels that govern the intrinsic properties of neurons.

Therefore, understanding how oAβ42 alters learning and memory is to understand how oAβ42 interacts with these channels.

Heterologous expression systems to study ion channel single-channel function

We utilize a concatenated subunit approach to heterologously ion channels with defined stoichiometries in model cell lines, allowing us to investigate how oAβ42 alters the single-channel properties of ion channels expressed by BFCNs.

Whole-cell patch clamp electrophisology

Using whole-cell patch clamp electrophysiology, we investigate whether the selective vulnerability of BFCNs in Alzheimer's disease arises from oAβ42-induced modulation of ion channels that govern intrinsic neuronal excitability.

Next generation RNA sequencing

We use cell type-specific RNA sequencing to determine how distinct neuronal populations alter their gene expression profiles in response to AD-related stressors and how these transcriptional changes contribute to selective neuronal vulnerability and pathological disruptions in neuronal excitability.

Cell-type specific gene knockdown and behavioral testing

To determine the behavioral consequences of oAβ42-induced ion channel dysfunction, we employ AAV-mediated, cell type-specific knockdown of ion channel genes to assess their contribution to oAβ42-driven alterations in BFCN excitability and the associated behavioral deficits. These studies are designed to identify the ion channel mechanisms that link oAβ42 pathology to disruptions in neuronal function and cognition.

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