Boosting the Brain’s Trash Removal System to Combat Alzheimer’s

Published on March 24, 2022

Imagine a bustling city with busy streets and sidewalks, where people are constantly discarding trash. Over time, if the garbage isn’t properly cleared away, it starts to pile up and create a messy, unsightly environment. The same can happen in the brain of someone with Alzheimer’s disease. In this study, scientists used a special fly model to mimic key aspects of Alzheimer’s pathology and see how they could clean up the mess. They found that a specific protein called human Nmnat1 was particularly effective at reducing the buildup of harmful proteins called amyloid plaques, one of the hallmarks of the disease. The researchers discovered that hNmnat1 achieved this by promoting a process called autophagic clearance, which is like a sophisticated recycling system that helps remove unwanted cellular debris. These exciting findings open up new possibilities for developing treatments that target hNmnat1 and enhance the brain’s natural garbage disposal capabilities. To learn more about this groundbreaking research, click on the link!

Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by irreversible cognitive decline with limited therapeutic approaches. We characterized a Drosophila model of amyloid pathology that expresses human amyloid-beta precursor protein (APP695) and β-site APP cleaving enzyme (BACE) in the nervous system. Our model recapitulates in vivo the age-dependent accumulation of BACE-derived C-terminal fragment (CTF) and amyloid plaques in the brain, one of the key pathological hallmarks of AD. Using this model, we assessed the effects on plaque formation of Nicotinamide mononucleotide adenylyltransferase (Nmnat), an evolutionarily conserved nicotinamide adenine dinucleotide (NAD+) synthase involved in cellular metabolism and neuroprotection. We compared the effects of overexpression of Drosophila Nmnat (dNmnat), human Nmnat1 (hNmnat1), human Nmnat2 (hNmnat2), and human Nmnat3 (hNmnat3), and observed that hNmnat1 has the highest efficacy in reducing amyloid aggregation and APP-CTF accumulation. Interestingly, we demonstrated that overexpression of hNmnat1 reduces amyloid plaques by promoting autophagic clearance. Our findings uncover a role of hNmnat1 in amyloid clearance and suggest an exciting neuroprotective potential of hNmnat1 in amyloid pathology.

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