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. 2025 Jun;21(6):e70339.
doi: 10.1002/alz.70339.

Cell-specific protein expression in Alzheimer's disease prefrontal cortex

Maryam Gholampour  1   2 , Malay K Basu  1 , Russell H Swerdlow  2   3 , Xinming Zhuo  4 , Mohammad Haeri  1   2
Affiliations

Cell-specific protein expression in Alzheimer's disease prefrontal cortex

Maryam Gholampour et al. Alzheimers Dement. 2025 Jun.

Abstract

Introduction: Analyzing the proteomes of different brain cell types is fundamental for understanding the pathophysiology of Alzheimer's disease (AD). However, spatial analysis of these diverse and limited cell populations poses significant challenges.

Methods: The GeoMx Digital Spatial Profiler (DSP) platform was used to analyze protein level in the prefrontal cortex of AD and non-AD brains. The platform interrogated 76 proteins and used immunofluorescence to distinguish between three cell types.

Results: Neprilysin (NEP), which promotes amyloid beta degradation, was significantly higher in AD neurons and microglia. Lysosome-associated membrane protein 2A (LAMP2A) level was higher in neurons of individuals with AD compared to a control group. In addition, markers of neuroinflammation, such as CD11c, CD11b, and CD163, were also elevated in AD neurons.

Discussion: Our findings indicate the DSP platform effectively facilitates cell-specific snapshots of the AD brain proteome.

Highlights: The expression of 76 proteins was studied in neurons, astrocytes, and microglia. We identified 18 differentially expressed proteins in AD neurons. Neprilysin was upregulated in neurons and microglia.

Keywords: Alzheimer's disease; GeoMx DSP; brain cell types; neprilysin; spatial proteomics.

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Conflict of interest statement

The authors declare no conflicts of interest. Author disclosures are available in the Supporting Information.

Figures

FIGURE 1
FIGURE 1
(A) Multicolor immunofluorescence localizes the expression of specific markers GFAP, NeuN, and Iba1 in AD postmortem FFPE tissue. (B) Distribution of cell types in eight ROIs from AD and controls. AD, Alzheimer's disease; FFPE, formalin‐fixed, paraffin‐embedded; GFAP, glial fibrillary acidic protein; Iba1, ionized calcium‐binding adapter molecule 1; NeuN, neuronal nuclei; ROIs, regions of interest.
FIGURE 2
FIGURE 2
Volcano plot of differential expression of proteins in neurons (A), microglia (B), and astrocytes (C) between the AD and control brains (The threshold criteria for statistical significance, p.adj < 0.05 and |FC| > 1.5, were considered significant and are shown as dashed gray lines. Proteins with significant changes are color‐coded: magenta for neurons and red for microglia). AD, Alzheimer's disease; GFAP, glial fibrillary acidic protein; NeuN, neuronal nuclei; Iba1, ionized calcium‐binding adapter molecule 1.
FIGURE 3
FIGURE 3
Box plots of significant protein targets in different cell types between AD and control (* p.adj ≤0.05). AD, Alzheimer's disease; GFAP, glial fibrillary acidic protein; NeuN, neuronal nuclei; Iba1, ionized calcium‐binding adapter molecule 1.
FIGURE 4
FIGURE 4
Power analysis across cell types and sample sizes.
See this image and copyright information in PMC

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