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The first Monday of each month, the Knight Initiative for Brain Resilience will host monthly seminars to bring together awardees, affiliated professors and students for a series of 'lab meeting' styled talks. Two speakers will discuss their brain resilience research, experiences in the field, and answer questions about their work.
Michael Haney, Stanford University
Microglia accumulate neurotoxic lipids in Alzheimer’s disease in an APOE dependent manner
Several genetic risk factors for Alzheimer’s Disease (AD) implicate genes involved in lipid metabolism and many of these lipid genes are specifically expressed in glial cells. However, the relationship between lipid metabolism in glia and AD pathology remains poorly understood. Through single-nucleus RNA-sequencing AD brain tissue, we have identified a microglial state defined by the expression of the lipid droplet associated enzyme ACSL1 with ACSL1 positive microglia most abundant in AD patients with the APOE4/4 genotype. In iPSC derived microglia (iMG) Aβ fibrils induce ACSL1 expression, triglyceride synthesis, and lipid droplet (LD) accumulation in an APOE dependent manner. Conditioned media from LD containing microglia leads to Tau phosphorylation and neurotoxicity. Our findings suggest a link between genetic risk factors for AD with microglial lipid accumulation and neurotoxic glial derived lipids in AD, potentially providing novel therapeutic strategies for AD.
Ravi Nath, Stanford University
A genetic screen of vertebrate aging identifies new regulators of lifespan
Can manipulation of neurons in the brain alter the body’s physiological state to extend lifespan? Neuropeptides are key modulators of short-term homeostasis such as feeding, temperature, and sleep. Whether neuropeptides could also control long-term physiology such as the rate of aging remains largely unknown. There has not been a systematic characterization of the role of neuropeptides in regulating vertebrate lifespan because lifespan experiments in vertebrates are slow (>2 years in mice). The African killifish is a promising vertebrate model system with a naturally compressed lifespan of 4-6 months. Using the killifish, I performed a targeted functional screen of 22 human-conserved neuropeptides and found 3 mutants with an increased lifespan. One of the strongest lifespan-extending neuropeptides interacts directly with the immune system and has key roles in regulating stress, suggesting that neuro-immune interactions and stress may be critical factors in longevity. These data indicate that neuropeptides are an important class of lifespan-regulating genes and presents new neuropeptidergic strategies to counter aging and extend healthy lifespan.
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