SPARCL1 Accelerates Symptom Onset in Alzheimer’s Disease and Influences Brain Structure and Function During Aging

Abstract

We recently reported that alpha-2 macroglobulin (A2M) is a biomarker of neuronal injury in Alzheimer’s disease (AD) and identified a network of nine genes co-expressed with A2M in the brain. This network includes the gene encoding SPARCL1, a protein implicated in synaptic maintenance. Here, we examine whether SPARCL1 is associated with longitudinal changes in brain structure and function in older individuals at risk for AD in the Baltimore Longitudinal Study of Aging. Using data from the Gene-Tissue Expression Project, we first identified two single nucleotide polymorphisms (SNPs), rs9998212 and rs7695558, associated with lower brain SPARCL1 gene expression. We then analyzed longitudinal trajectories of cognitive performance in 591 participants who remained cognitively normal (average follow-up interval: 11.8 years) and 129 subjects who eventually developed MCI or AD (average follow-up interval: 9.4 years). Cognitively normal minor allele carriers of rs7695558 who developed incident AD showed accelerated memory loss prior to disease onset. Next, we compared longitudinal changes in brain volumes (MRI; n = 120 participants; follow-up = 6.4 years; 826 scans) and resting-state cerebral blood flow (rCBF; 15O-water PET; n = 81 participants; follow-up = 7.7 years; 664 scans) in cognitively normal participants. Cognitively normal minor allele carriers of rs9998212 showed accelerated atrophy in several global, lobar, and regional brain volumes. Minor allele carriers of both SNPs showed longitudinal changes in rCBF in several brain regions, including those vulnerable to AD pathology. Our findings suggest that SPARCL1 accelerates AD pathogenesis and thus link neuroinflammation with widespread changes in brain structure and function during aging.

α2-Macroglobulin in Alzheimer’s Disease: New Roles for an Old Chaperone

“…Moreover, SPARCL1/hevin has recently been shown to play a key role in glutamatergic synaptogenesis during development [31]. We have recently shown that polymorphic variation in the SPARCL1 gene is associated with several AD endophenotypes, including accelerated cognitive decline, faster brain atrophy and altered neuronal activity in several brain regions [32]. Taken together, our findings suggest that SPARCL1 and A2M may respond to neuronal injury in preclinical AD.…”

Dysregulation of Exosome Cargo by Mutant Tau Expressed in Human-induced Pluripotent Stem Cell (iPSC) Neurons Revealed by Proteomics Analyses

“…The hub proteins of JUP (102) and GD12 (103) bind to presenilin-1, a component of ␥-secretase. SPARC1 is a protein involved in synaptic maintenance and is associated with age-related changes in brain structure (104).…”

Large-scale proteomic analysis of human prefrontal cortex identifies proteins associated with cognitive trajectory in advanced age

“…For each cohort, we model the annual MMSE score as a longitudinal outcome, follow-up year as the independent variable and sex, age at enrollment, and education as the covariates, with a random intercept and random slope per subject using the lme4 R package (version 1. [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19]. The derived cognitive trajectory for each individual in Banner and BLSA cohorts is listed in supplementary table 1.…”