# Transcriptomic and Circuitry Aberrations in Alzheimer’s Disease

> **NIH NIH R01** · STATE UNIVERSITY OF NEW YORK AT BUFFALO · 2024 · $741,733

## Abstract

Project Summary
In Alzheimer’s disease (AD) research, a big challenge is the identification and targeting of key molecules in
critical neural circuits that play a causal role in cognitive impairment at the early stage before global
neurodegeneration. We hypothesize that transcriptional downregulation of selective neuronal genes in early AD
initiates the loss of synaptic function in specific brain circuits, leading to cognitive decline. In Aim 1, we will identify
transcriptomic changes at the early stage of AD using human postmortem tissues and iPSC-derived cortical
neurons. Comprehensive bioinformatic analyses of large-scale bulk and single-cell RNAseq data from
postmortem human with ‘early-pathology’ and ‘late-pathology’ of AD will be performed to identify prominent
changes in gene networks, molecular pathways and biological processes at different stages. Given the limitation
of postmortem tissues in capturing early molecular alterations, we will also profile transcriptional changes using
human cortical neurons differentiated from iPSCs of sporadic AD patients. Based on our preliminary data, the
loss of selective presynaptic and postsynaptic genes involved in vesicle release and glutamatergic/GABAergic
transmission is the major early change in cortical neurons of AD patients. In Aim 2, we will identify
electrophysiological changes using AD mouse models and iPSC-derived cortical neurons from AD patients. We
will use in vivo multichannel recording of action potential spikes, optogenetic isolation of neural pathways and
ex vivo patch-clamp recording of synaptic currents in AD mouse models to obtain the high-resolution mapping
of cognitive circuits that go awry at various stages. In Aim 3, we will identify intervention strategies to rescue AD-
associated functional deficits in AD mouse models and iPSC-derived cortical neurons from AD patients. Guided
by the identified molecular and circuitry changes in AD, we will use viral-based approaches to normalize gene
expression or neuronal activity in specific circuits, and examine the impact on synaptic transmission and
cognitive behaviors in AD mouse models. This study will uncover transcriptomic and circuitry aberrations in early
stage of AD, and help to develop mechanism-based therapeutic strategies to mitigate synaptic deficits and
improve cognition.

## Key facts

- **NIH application ID:** 10745295
- **Project number:** 5R01AG079797-02
- **Recipient organization:** STATE UNIVERSITY OF NEW YORK AT BUFFALO
- **Principal Investigator:** JIAN FENG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $741,733
- **Award type:** 5
- **Project period:** 2022-12-01 → 2027-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10745295

## Citation

> US National Institutes of Health, RePORTER application 10745295, Transcriptomic and Circuitry Aberrations in Alzheimer’s Disease (5R01AG079797-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10745295. Licensed CC0.

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