David Bennett

2 months ago | cell.com | Milene Vandal |Adam Institoris |Louise Reveret |Ben Korin |Colin Gunn |Sotaro Hirai | +30 more

KeywordsAlzheimercerebrovascular functionsexual dimorphismbrain endothelial cellsCD2APreelinAβApoER2/LRP8endothelin-1mural cellsGet full text accessLog in, subscribe or purchase for full access. References1. Schaeffer, S. ∙ Iadecola, C. Revisiting the neurovascular unitNat Neurosci. 2021; 24:1198-12092. Korte, N. ∙ Nortley, R. ∙ Attwell, D. Cerebral blood flow decrease as an early pathological mechanism in Alzheimer’s diseaseActa Neuropathol. 2020; 140:793-8103. Yang, A.C. ∙ Vest, R.T. ∙ Kern, F. ...

Jun 11, 2024 | nature.com | Serafima Dubnov |Nadav Yayon |Or Yakov |David Bennett |Sudha Seshadri |Elliott J. Mufson | +7 more

Overexpression of the longevity gene Klotho prolongs lifespan, while its knockout shortens lifespan and impairs cognition via perturbation of myelination and synapse formation. However, comprehensive analysis of Klotho knockout effects on mammalian brain transcriptomics is lacking. Here, we report that Klotho knockout alters the levels of aging- and cognition related mRNAs, long non-coding RNAs, microRNAs and tRNA fragments. These include altered neuronal and glial regulators in murine models of aging and Alzheimer’s disease and in human Alzheimer’s disease post-mortem brains. We further demonstrate interaction of the knockout-elevated tRNA fragments with the spliceosome, possibly affecting RNA processing. Last, we present cell type-specific short RNA-seq datasets from FACS-sorted neurons and microglia of live human brain tissue demonstrating in-depth cell-type association of Klotho knockout-perturbed microRNAs. Together, our findings reveal multiple RNA transcripts in both neurons and glia from murine and human brain that are perturbed in Klotho deficiency and are aging- and neurodegeneration-related. Transcriptomic profiling shows that Klotho knockout perturbs brain short non-coding RNAs, such as microRNA and tRNA fragments, in both neurons and glia, that mimics the changes associated with Alzheimer’s disease and aging in humans and murine models.