McNair, E. | bioRxiv Science

bioRxiv2024

Microglia promote neurodegeneration and hyperkatifeia during withdrawal and prolonged abstinence from chronic binge alcohol

Proinflammatory microglial polarization, neuronal death, and hyperkatifeia/negative affect during withdrawal are key features of alcohol use disorder (AUD). However, the role microglia play in the development of AUD-related neuronal and behavioral pathology is unclear. Given the ability of microglia to regulate neuronal function, it was hypothesized that proinflammatory microglia promote neuronal death and hyperkatifeia during prolonged abstinence from binge alcohol. Proinflammatory signaling and affective state were assessed in mice either during acute withdrawal (24h) or abstinence (>4 weeks) to binge alcohol exposure. Ten days of binge alcohol increased proinflammatory gene signaling 24h after EtOH, which lasted weeks into withdrawal. Alcohol reduced brain-derived neurotrophic factor (BDNF) in hyperkatifeia-associated regions (i.e., the central amygdala and infralimbic cortex) during acute withdrawal and caused persistent microglial structural changes and loss of microglial BDNF in the BNST during abstinence. This was associated with increased anxiety-like behavior and hyperarousal, with persistent enhancement of conditioned fear memory during abstinence. Inhibition of proinflammatory microglia with Gi designer receptors exclusively activated by designer drugs (DREADDs) blocked neuronal death and prevented persistent proinflammatory gene induction and hyperkatifeia in female mice. Thus, this identifies a direct role for microglia in the development of AUD-related neuropathology and behavioral dysfunction, implicating microglia as cellular targets for the prevention of AUD phenotypes.

neuroscience↗

bioRxiv2024

Loss of neuronal lysosomal acid lipase drives amyloid pathology in Alzheimer's disease

Underlying drivers of late-onset Alzheimers disease (LOAD) pathology remain unknown. However, multiple biologically diverse risk factors share a common pathological progression. To identify convergent molecular abnormalities that drive LOAD pathogenesis we compared two common midlife risk factors for LOAD, heavy alcohol use and obesity. This revealed that disrupted lipophagy is an underlying cause of LOAD pathogenesis. Both exposures reduced lysosomal flux, with a loss of neuronal lysosomal acid lipase (LAL). This resulted in neuronal lysosomal lipid (NLL) accumulation, which opposed A{beta} localization to lysosomes. Neuronal LAL loss both preceded (with aging) and promoted (targeted knockdown) A{beta} pathology and cognitive deficits in AD mice. The addition of recombinant LAL ex vivo and neuronal LAL overexpression in vivo prevented amyloid increases and improved cognition. In WT mice, neuronal LAL declined with aging and correlated negatively with entorhinal A{beta}. In healthy human brain, LAL also declined with age, suggesting this contributes to the age-related vulnerability for AD. In human LOAD LAL was further reduced, correlated negatively with A{beta}1-42, and occurred with polymerase pausing at the LAL gene. Together, this finds that the loss of neuronal LAL promotes NLL accumulation to impede degradation of A{beta} in neuronal lysosomes to drive AD amyloid pathology. SummaryCellular and molecular drivers of late-onset Alzheimers disease (LOAD) are unknown, though several risk factors account for the majority of disease incidence1-5. Though diverse in their biological natures, each of these risk exposures converge on a shared pathological progression with the accumulation of amyloid early in the disease. Human genetic and transcriptomic studies suggest a role for altered lipid metabolism6-9, though the mechanism has been unknown. Here, using two common midlife risk exposures for LOAD, we found that dysfunctional lipophagy caused by the loss of lysosomal acid lipase (LAL) promotes early LOAD pathogenesis. Both midlife obesity and heavy alcohol reduced neuronal LAL, causing an increase in neuronal lysosomal lipid, and a subsequent accumulation of A{beta} in the extra-lysosomal cytosol. This loss of LAL preceded and promoted A{beta} pathology and cognitive deficits in AD mice. The addition of recombinant LAL ex vivo and neuronal LAL overexpression in vivo prevented increases in amyloid and improved cognition. In human brain, LAL declined with age in healthy subjects, similar to rodents, showing robust losses in LOAD subjects with polymerase pausing. Together, this implicates neuronal LAL loss in LOAD pathogenesis and presents LAL as a promising diagnostic, preventative, and/or therapeutic target for AD.

neuroscience↗