# Mass spectrometry and multiplexed immunofluorescence imaging of metabolic and proteomic contributors to selective neuronal vulnerability in Alzheimer's disease

> **NIH NIH R01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2022 · $880,858

## Abstract

We aim to uncover metabolic and protein signaling pathways contributing to the regional vulnerability of
neocortical pyramidal neurons in Alzheimer's disease and to identify novel targets for detection and
intervention. We will compare the prefrontal cortex, a neocortical brain area afflicted by neuropathology
early in Alzheimer's disease, with the primary visual cortex, a brain area that is relatively spared. We will
use mass spectrometric imaging in combination with segmentation analyses, to identify spatial changes
of small molecules and proteins in postmortem brain sections prepared from these neocortical areas from
donors at various clinical and pathological stages of Alzheimer's disease compared to controls. Then, we
will apply multiplexed immunofluorescence imaging on sequential sections from the same specimens, to
obtain information on cellular and microenvironment changes in and around vulnerable neocortical
neurons during disease progression, correlated with the clinical severity, degree and location of
neuropathological changes, and the risk genotype. Further, we will register the data from both imaging
techniques to identify metabolic pathways and protein signaling changes at the regional, laminar and
cellular level and to locate covariation in molecular and cellular phenotypes contributing to Alzheimer's
disease vulnerability. In addition to generating a comprehensive dataset of the cellular and molecular
changes at various stages of Alzheimer's disease, these studies will involve the development, validation,
and dissemination of novel tools for analysis of large datasets generated using two powerful imaging
tools, one that detects hundreds of analytes with the possibility of detecting previously unknown
contributors to disease and the other that provides higher resolution with a select set of known markers.
In the long term, the data generated from these studies could provide the basis for testing novel disease-
modifying treatments by cell-type specific targeting of identified metabolic pathways using experimental
models, such as brain organoids to replicate cortical lamination with human neurons or humanized mouse
chimeras to model interactions between neurons and non-neuronal cell types.

## Key facts

- **NIH application ID:** 10515902
- **Project number:** 1R01AG078755-01
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** PARAG Kumar MALLICK
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $880,858
- **Award type:** 1
- **Project period:** 2022-09-15 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10515902

## Citation

> US National Institutes of Health, RePORTER application 10515902, Mass spectrometry and multiplexed immunofluorescence imaging of metabolic and proteomic contributors to selective neuronal vulnerability in Alzheimer's disease (1R01AG078755-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10515902. Licensed CC0.

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