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Oveisgharan, S.

Publications and source records attributed to Oveisgharan, S..

2 recordsLinked to original sources
bioRxiv2026

Post-translational modifications in the brain are critical contributors to Alzheimers disease neuropathology and cognitive decline

Post-translational modifications (PTMs) in APP and MAPT contribute to plaques and tangles in Alzheimers disease (AD). Yet broader proteome-wide PTMs in the AD brain are relatively unexplored. Therefore, this study highlights associations between PTMs, quantified by mass spectrometry in prefrontal cortex tissue, and Alzheimers disease neuropathology and cognition. Leveraging PTMs quantified from prefrontal cortices in 101 Rush Memory and Aging Project participants. We assessed associations with post-mortem amyloid-{beta} and tau burden, global cognition, and cognitive decline. First, APP and MAPT PTM associations were assessed on these outcomes given their known relevance in AD, followed by assessment of protein-wide effects of PTMs. Then, kinase enrichment analysis was performed on each outcome to assess which kinases might contribute to the results. We observed a novel association of APP-K687 acetylation, a known mutation hotspot driving pathology, with amyloid-{beta} load ({beta}=0.44, P=3.9e-8), while confirming known MAPT PTMs with tangle burden. Further, we identified 20+ novel PTMs associations with AD neuropathology, including ENO2-K256 ubiquitination ({beta}=0.353, P=1.13e-6), PSMD13-K31 ubiquitination ({beta}=0.568, P=1.34e-6), and PLXND1-K1826 ubiquitination ({beta}=0.577, P=7.08e-8) for tangle burden and SYP-K23 ubiquitination ({beta}=1.50, P=4.7e-8), TMEFF2-C80 cysteine oxidation ({beta}=1.64, P=1.1e-8), and STX1B-T121 phosphorylation ({beta}=0.898, P=3.3e-7) for amyloid-{beta} load. Further, kinase enrichment analyses highlight the complexity of disease-related proteome changes with some kinases like CDK5 showing expected over-enrichment (amyloid z=3.44, P=3.0e-4; tau z=4.98, P=3.3e-7) but others like PKC family kinases showing divergent enrichment between amyloid (z=8.98-11.55, P<1.0e-18) and tau (z=-2.83--3.88, P<0.006). This study provides an atlas of brain PTMs within crucial proteins like MAPT and APP and at the proteome-wide level, that impact AD neuropathology and clinical presentation. Further, we explored what kinases might be driving phosphorylation results, emphasizing the complex proteome changes which impact AD. In sum, these results highlight robust post-translational alterations in the AD brain and provide novel targets for future mechanistic studies.

neuroscience↗
bioRxiv2026

Multi-omics characterization of vascular, neurodegenerative, and mixed neuropathology in the aging human brain

Late-life cognitive impairment most commonly occurs in the setting of mixed neurodegenerative and cerebrovascular pathology, yet the molecular programs distinguishing vascular, neurodegenerative, and mixed pathology in the aging human brain remain incompletely defined. We performed neuropathology-stratified proteomic and transcriptomic profiling of postmortem brain tissue from participants in the Religious Orders Study and Rush Memory and Aging Project. Dorsolateral prefrontal cortex proteomics (n = 733) were analyzed alongside bulk RNA sequencing from dorsolateral prefrontal cortex (n = 938), posterior cingulate cortex (n = 569), and anterior caudate (n = 632). Participants were classified into vascular, neurodegenerative, and mixed pathology groups based on comprehensive autopsy assessment. Neurodegenerative and mixed pathology, relative to vascular pathology, showed coordinated upregulation of immune and inflammatory pathways and downregulation of mitochondrial and oxidative phosphorylation programs across molecular layers. Although few individual proteins differed between mixed and neurodegenerative groups, pathway-level analyses identified additional remodeling programs in mixed pathology, including extracellular matrix organization and vesicle-mediated transport. Proteomic co-expression network analysis identified immune-stress modules associated with amyloid burden, tau pathology, and cognitive decline, whereas a mitochondrial bioenergetic module showed relative preservation in vascular pathology. Cross-omics concordance was robust at the pathway level but limited at the level of individual genes and proteins. These findings define conserved molecular programs distinguishing vascular, neurodegenerative, and mixed pathology and demonstrate that pathway-level organization provides a stable framework for interpreting molecular heterogeneity in late-life dementia.

genomics↗