Biology subjects

Reich, L.

Publications and source records attributed to Reich, L..

2 recordsLinked to original sources

bioRxiv2023

Single-cell multiomic analysis reveals the involvement of Type I interferon-responsive CD8+ T cells in amyloid beta-associated memory loss

Alzheimers disease (AD) is the leading cause of dementia worldwide, but there are limited therapeutic options and no current cure. While the involvement of microglia in AD has been highly appreciated, the role of other innate and adaptive immune cells remains largely unknown, partly due to their scarcity and heterogeneity. This study aimed to study non-microglial immune cells in wild type and AD-transgenic mouse brains across different ages. Our results uncovered the presence of a unique CD8+ T cell population that were selectively increased in aging AD mouse brains, here referred to as "disease-associated T cells (DATs)". These DATs were found to express an elevated tissue-resident memory and Type I interferon-responsive gene signature. Further analysis of aged AD mouse brains showed that these CD8+ T cells were not present in peripheral or meningeal tissues. Preventing CD8+ T cell development in AD-transgenic mice via genetic deletion of beta-2 microglobulin (B2m) led to a reduction of amyloid-{beta} plaque formation in aged mice, and improved memory in AD-transgenic mice as early as four months of age. The integration of transcriptomic and epigenomic profiles at the single-cell level revealed potential transcription factors that reshape the regulomes of CD8+ T cells. These findings highlight a critical role for DATs in the progression of AD and provide a new avenue for treatment.

immunology↗

bioRxiv2022

The carnitine shuttle links mitochondrial metabolism to histone acetylation and lipogenesis

Acetyl-CoA is a central metabolite used for lipid synthesis in the cytosol and histone acetylation in the nucleus, among other pathways. The two major precursors to acetyl-CoA in the nuclear-cytoplasmic compartment are citrate and acetate, which are processed to acetyl-CoA by ATP-citrate lyase (ACLY) and acyl-CoA synthetase short-chain 2 (ACSS2), respectively. While some evidence has suggested the existence of additional routes to nuclear-cytosolic acetyl-CoA, such pathways remain poorly defined. To investigate this, we generated cancer cell lines lacking both ACLY and ACSS2. Unexpectedly, and in contrast to observations in fibroblasts, ACLY and ACSS2 double knockout (DKO) cancer cells remain viable and proliferate, maintain pools of cytosolic acetyl-CoA, and are competent to acetylate proteins in both cytosolic and nuclear compartments. Using stable isotope tracing, we show that both glucose and fatty acids feed acetyl-CoA pools and histone acetylation in DKO cells. Moreover, we provide evidence for the carnitine shuttle and carnitine acetyltransferase (CrAT) as a substantial pathway to transfer two-carbon units from mitochondria to cytosol independent of ACLY. Indeed, in the absence of ACLY, glucose can feed fatty acid synthesis in a carnitine responsive and CrAT-dependent manner. This work defines a carnitine-facilitated route to produce nuclear-cytosolic acetyl-CoA, shedding light on the intricate regulation and compartmentalization of acetyl-CoA metabolism

cell biology↗