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. 2024 Jan;20(1):525-537.
doi: 10.1002/alz.13474. Epub 2023 Sep 19.

Associations of cortical SPP1 and ITGAX with cognition and common neuropathologies in older adults

Katia de Paiva Lopes  1   2 , Lei Yu  1   2 , Xianli Shen  3   4 , Yiguo Qiu  3   4   5 , Shinya Tasaki  1   2 , Artemis Iatrou  1   2   6 , Michal Schnaider Beeri  7   8   9 , Nicholas T Seyfried  10 , Vilas Menon  11 , Yanling Wang  1   2 , Julie A Schneider  1   2   12 , Harvey Cantor  3   4 , David A Bennett  1   2
Affiliations

Associations of cortical SPP1 and ITGAX with cognition and common neuropathologies in older adults

Katia de Paiva Lopes et al. Alzheimers Dement. 2024 Jan.

Abstract

Introduction: The secreted phosphoprotein 1 (SPP1) gene expressed by CD11c+ cells is known to be associated with microglia activation and neuroinflammatory diseases. As most studies rely on mouse models, we investigated these genes and proteins in the cortical brain tissue of older adults and their role in Alzheimer's disease (AD) and related disorders.

Methods: We leveraged protein measurements, single-nuclei, and RNASeq data from the Religious Orders Study and Rush Memory and Aging Project (ROSMAP) of over 1200 samples for association analysis.

Results: Expression of SPP1 and its encoded protein osteopontin were associated with faster cognitive decline and greater odds of common neuropathologies. At single-cell resolution, integrin subunit alpha X (ITGAX) was highly expressed in microglia, where specific subpopulations were associated with AD and cerebral amyloid angiopathy.

Discussion: The study provides evidence of SPP1 and ITGAX association with cognitive decline and common neuropathologies identifying a microglial subset associated with disease.

Keywords: CD11c; ITGAX; OPN; RNASeq; SPP1; cognition; microglia; neuropathologies; osteopontin; snRNASeq.

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Conflict of interest statement

N.T.S. is a co‐founder of a company called Emtherapro. The other authors declare no conflicts of interest.

Figures

FIGURE 1
FIGURE 1
Schematic of the study. We analyzed three distinct layers of omics data from the dorsolateral prefrontal cortex brain region: bulk RNASeq (N = 1206), TMT protein measurements (N = 580), and snRNASeq (N = 424), plus a replication analysis with external datasets. Figure created with Biorender. ITGAX, integrin subunit alpha X; MSBB, Mount Sinai Brain Bank; ROSMAP, Religious Orders Study and Rush Memory and Aging Project; SPP1, secreted phosphoprotein 1; TMT, tandem mass tag
FIGURE 2
FIGURE 2
The associations of secreted phosphoprotein 1 (SPP1) and integrin subunit alpha X (ITGAX) genes and their encoded proteins with cognitive decline. (A,B) Associations of SPP1 and osteopontin (OPN) with cognitive decline. (C,D) Associations of ITGAX and CD11c with cognitive decline. Red: high gene/protein expression; black: average gene/protein expression; blue: low gene/protein expression.
FIGURE 3
FIGURE 3
Associations of secreted phosphoprotein 1 (SPP1) and integrin subunit alpha X (ITGAX) expression with neuropathologies. (A,B) SPP1 gene and its protein, osteopontin (OPN). (C‐D) ITGAX gene and its protein, CD11c. For each neuropathologic index tested, the horizontal line represents the odds ratio (OR) and 95% confidence interval (CI). Dashed vertical line highlights the cutoff for significant association. AD, Alzheimer's disease; Arterio, arteriolosclerosis; CAA, cerebral amyloid angiopathy; CVDA, atherosclerosis; HS, hippocampal sclerosis; LATE, limbic‐predominant age‐related TDP‐43 encephalopathy
FIGURE 4
FIGURE 4
Expression level of secreted phosphoprotein 1 (SPP1) and integrin subunit alpha X (ITGAX) and neuropathologies association analysis by cell type. (A) Expression level of the ITGAX and SPP1 genes by cell type (cell types: ast = astrocytes, ext = excitatory neurons, inh = inhibitory neurons, mic = microglia, oli = oligodendrocytes, and OPCs = oligodendrocyte precursor cells). (B) The associations of gene expression and neuropathologies, by cell type. Red represents a positive association. AD, Alzheimer's disease; CAA, cerebral amyloid angiopathy; Est, estimate; HS, hippocampal sclerosis; LATE, limbic‐predominant age‐related TDP‐43 encephalopathy; LB, Lewy bodies
FIGURE 5
FIGURE 5
Neuropathologies association analysis for the microglia sub‐clusters. (A) Association of secreted phosphoprotein 1 (SPP1) gene expression and neuropathologic indexes for the microglial subpopulations. (B) Association of integrin subunit alpha X (ITGAX) gene expression and neuropathologic indexes for the microglial subpopulations. Red represents a positive association (ie, higher expression is associated with more or higher odds of the pathology). AD, Alzheimer's disease; CAA, cerebral amyloid angiopathy; Est, estimate; HS, hippocampal sclerosis; LATE, limbic‐predominant age‐related TDP‐43 encephalopathy; LB, Lewy bodies; mic, microglia
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