Browsing by Author "Kumar, Subodh"

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    Elevated brain miR298 is associated with a reduced risk of Alzheimer’s disease
    (Wiley, 2025-01-03) Lahiri, Debomoy K.; Wang, Ruizhi; Maloney, Bryan; Ghetti, Bernardino; Saykin, Andrew J.; Kumar, Subodh; White, Fletcher A.; Greig, Nigel H.; Sambamurti, Kumar; Counts, Scott E.; Psychiatry, School of Medicine
    Background: Non‐coding RNA species, such as microRNA (miRNA), regulate multiple biological and pathological processes by binding to target mRNAs and facilitating alteration of translation levels via complexes such as RNA‐induced silencing complex (RISC). Disrupting this process could contribute to AD pathogenesis by fostering aggregation of hyperphosphorylated microtubule‐associated protein tau and amyloid‐β (Aβ) peptides, and neuroinflammation. Understanding how these pathological changes are regulated remains our research focus. We report that miR298 plays a vital role in maintaining APP and tau homeostasis and that miR298 imbalances may impact AD progression. Method: Levels of miR298 from non‐cognitively impaired (NCI) and AD subject brain tissue samples from different recognized sources were measured by qRT‐PCR and assessed for associations with AD risk and potential covariates such as age and APOE genotype. Other biomarkers were assessed in cortical samples from the same subjects, as we previously described. Further, APP, tau, and cytokines were profiled in miR298 mimic‐ or its antagomiR‐expressing human neuronal and astrocyte cultures. Result: Levels of miR298 varied in postmortem temporal lobe between AD patients and age‐matched NCI controls. Higher brain miR298 levels were associated with a reduced risk of AD. Subject age and APOE genotype altered this association; specifically, greater age and dose of the APOEε4 allele were associated with an increased risk of AD. However, APOEε4 dose‐associated risk reduced as age increased. We identified putative binding sites for miR298 on APP, BACE1, MAPT, IL1α, and IL6 mRNAs to form RISC. We showed that treatment by miR298 reduced tau, APP, and BACE1 proteins and mRNA levels in cell cultures. Conclusion: These studies suggest that miR298 regulates a coordinated network of AD‐related proteins APP, BACE1, and tau. Hence, such network regulation may represent a rational therapeutic target for reducing AD risk and disease modification. In addition to late‐onset cases, we will profile miR298 in brain tissue samples from early‐onset AD cases. Future work involves testing miR298 in AD animal models, such as in human tau‐overexpressing transgenic mice. We sincerely thank grant support from NIA/NIH.
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    Synaptosome microRNAs regulate synapse functions in Alzheimer's disease
    (Springer Nature, 2022-08-08) Kumar, Subodh; Orlov, Erika; Gowda, Prashanth; Bose, Chhanda; Swerdlow, Russell H.; Lahiri, Debomoy K.; Reddy, P. Hemachandra; Psychiatry, School of Medicine
    MicroRNAs (miRNAs) are found in nerve terminals, synaptic vesicles, and synaptosomes, but it is unclear whether synaptic and cytosolic miRNA populations differ in Alzheimer's disease (AD) or if synaptosomal miRNAs affect AD synapse activity. To address these questions, we generated synaptosomes and cytosolic fractions from postmortem brains of AD and unaffected control (UC) samples and analyzed them using a global Affymetrix miRNAs microarray platform. A group of miRNAs significantly differed (P < 0.0001) with high fold changes variance (+/- >200-fold) in their expressions in different comparisons: (1) UC synaptosome vs UC cytosol, (2) AD synaptosomes vs AD cytosol, (3) AD cytosol vs UC cytosol, and (4) AD synaptosomes vs UC synaptosomes. MiRNAs data analysis revealed that some potential miRNAs were consistently different across sample groups. These differentially expressed miRNAs were further validated using AD postmortem brains, brains of APP transgenic (Tg2576), Tau transgenic (P301L), and wild-type mice. The miR-501-3p, miR-502-3p, and miR-877-5p were identified as potential synaptosomal miRNAs upregulated with disease progression based on AD Braak stages. Gene Ontology Enrichment and Ingenuity Pathway Analysis of synaptosomal miRNAs showed the involvement of miRNAs in nervous system development, cell junction organization, synapse assembly formation, and function of GABAergic synapse. This is the first description of synaptic versus cytosolic miRNAs in AD and their significance in synapse function.