Browsing by Subject "AD pathogenesis"

Now showing 1 - 3 of 3
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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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    miRNA, transcriptional regulation and cognitive decline
    (Wiley, 2025-01-03) Fischer, Andre; Sananbenesi, Farahnaz; Nho, Kwangsik; Manfred Krüger, Dennis; Shaw, Leslie M.; Saykin, Andrew J.; Delalle, Ivana; Radiology and Imaging Sciences, School of Medicine
    Background: Despite significant advancements in the development of blood biomarkers for AD, challenges persist due to the complex interplay of genetic and environmental risk factors in AD pathogenesis. Epigenetic processes, including non‐coding RNAs and especially microRNAs (miRs), have emerged as important players in the molecular mechanisms underlying neurodegenerative diseases. MiRs have the ability to fine‐tune gene expression and proteostasis, and microRNAome profiling in liquid biopsies is gaining increasing interest since changes in miR levels can indicate the presence of multiple pathologies. We have profiled blood samples via smallRNA sequencing for 1056 individuals of the DELCODE and 847 individuals of the ANDI cohort. Methods: We profiled blood samples via smallRNA sequencing for 1056 individuals of the DELCODE (German Longitudinal Cognitive Impairment and Dementia Study) and 847 individuals of the ANDI (Aging and Dementia in the Community) cohort, consisting of individuals diagnosed with SCD, MCI, AD, or control. Results: By applying differential expression, WGCNA, as well as linear and non‐linear machine learning approaches, we identify microRNA signatures that can help identify patients at distinct stages of disease progression, as well as signatures that can predict the course of the disease. These data are compared with phenotyping data, such as cognitive function and ATN biomarkers. We will also discuss the role of other non‐coding RNAs besides microRNAs and provide a framework for developing RNA‐based point‐of‐care assays.
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    PAA, a novel metal chelator and metalloproteinase inhibitor significantly reduced amyloid plaque burden in an APP/tau mouse model of Alzheimer’s disease (AD)
    (Wiley, 2025-01-09) Schmued, Larry; Schmued, Calvert; Maloney, Bryan; Lahiri, Debomoy K.; Psychiatry, School of Medicine
    Background: Major contributors to AD pathogenesis include aggregates of amyloid‐β (Aβ) peptides, hyperphosphorylated tau protein, and neuroinflammation. No currently approved treatment stops or significantly slows the progression of AD. Nevertheless, one class of agents that has shown promise is metal chelators. For the assessment of a novel effect of oral administration of 1,10‐Phenanthroline‐5‐amine (PAA) on the severity of amyloid plaque load, we used a transgenic (Tg) mouse model with inserted human autosomally dominant (familial) AD genes: amyloid‐beta (Aβ) protein precursor (APP) and tau protein. Method: APP/Tau transgenic mice that model AD were allotted into one of two groups. The control group received no treatment while the experimental group received 1,10‐phenanthroline‐5‐amine (PAA) in their drinking water, starting at 4 months. All animals were sacrificed at 1 year of age, and their brains were stained with 2 different markers of amyloid plaques, Amylo‐Glo+ and HQ‐O, as we have recently described (Schmued et al, 2023). Result: PAA administered as a daily oral dose for 9 months resulted in no changes in weight or behavior and resulted in no observed pathologies. Control animals exhibited numerous dense core plaques throughout the neo‐ and allo‐cortical brain regions. PAA administered as a daily dose for 9 months resulted in roughly 2/3 the amyloid plaque burden compared to untreated transgenic mice. Conclusion: Oral daily dosing with PAA significantly reduced the amyloid plaque burden in transgenic AD model mice. The mode of action of PAA may be attributed to its ability to chelate transition metals and to inhibit either metalloprotease enzymes or the metal‐seeded auto aggregation of Aβ. The underlying mechanism for this protection is not fully known; one possible mechanism would be to inhibit the “metal‐seeding” of Aβ. Dyshomeostasis of certain transition metals in brain microenvironment contributes to amyloidosis. Although this dysregulation may be attributable to impaired metal transporter function, there exists no known treatment that would modify such dysfunction. Further research is underway to confirm these results in another mouse model of AD (APP/PS1). Altogether, reducing regional metal levels via chelation with PAA may be a feasible and viable strategy for suppressing the formation of amyloid plaques in AD patients.