A research collaboration between investigators from the Spanish National Research Council (CSIC), the Miguel Hernández University of Elche (UMH), and the École Polytechnique Fédérale de Lausanne (EPFL) has identified a molecule that may could be a new approach to treating Alzheimer’s disease (AD) by restoring the protective functions of microglia, immune cells found in the brain. The findings, published in Cell Death & Disease, said the molecule N-oleoyl-Leucine (OLE), which is derived from the Alzheimer’s disease-associated gene PM20D1, was shown to reduce amyloid pathology, improve cognition, and promote neuroprotection.
“One of the most significant findings is that we have identified a molecule capable of restoring microglia’s protective function,” said senior author José Vicente Sánchez Mut, PhD, principal investigator at the Functional Epi-Genomics of Aging and Alzheimer’s Disease laboratory at the Institute for Neurosciences, a joint CSIC-UMH center. “In Alzheimer’s disease, these cells become progressively impaired. Our results suggest that this process can be reversed, pointing to new therapeutic and research avenues to counteract the disease.”
In recent years, there has been a surge of research into microglia’s role in AD. As the researchers noted, genetic risk variants associated with AD are enriched in regions that regulate microglial function, and microglial gene-expression programs have been shown to be altered during disease progression. As the disease advances, microglia proliferate and accumulate around amyloid plaques, but lose their ability to maintain tissue homeostasis and clear amyloid beta (Aβ). At the same time these immune cells take on inflammatory and neurotoxic characteristics.
PM20D1 has been identified recently as a risk gene in the development of AD. It is a quantitative trait locus associated not only with Alzheimer’s disease but also with diabetes, obesity, and other disorders. People exhibiting lower PM20D1 expression have a higher risk of developing metabolic disorders and Alzheimer’s disease. Other prior research studies also showed that PM20D1 overexpression in mouse models reduced amyloid levels and cognitive deficits, making it a potentially fruitful area for additional study.
PM20D1 encodes a secreted enzyme that regulates the conjugation of fatty acids with amino acids, generating compounds known as N-acyl amino acids (NAAA). OLE is one of these amino acids and was selected for further investigation because PM20D1 activity in living organisms appears to favor its production and because OLE levels are strongly correlated with PM20D1 expression in both humans and mice.
“There is increasing evidence of microglia participation in Alzheimer’s disease (AD), which incentives their modulation to intercept the disease,” the researchers wrote. “Here, we describe a new mechanism by which the recently AD-associated Peptidase M20 Domain Containing 1 (PM20D1) instructs microglia to tackle AD.”
To evaluate OLE’s therapeutic potential, the team first tested it in genetically engineered Caenorhabditis elegans worms that produce beta-amyloid, where they showed that OLE treatment reduced protein aggregation and improved mobility. The researchers then administered OLE to APP/PS1 mouse models of AD for three months. Again, the mice demonstrated better performance in memory tests and showed reductions in amyloid plaque burden.
A cellular analyses found that microglia were the cells most responsive to OLE treatment.
“Single-cell analysis allowed us to determine that microglia were the cells that responded most strongly to the treatment,” said first author Victoria Pozzi, PhD, a postdoctoral researcher working in the Sánchez Mut lab. “From there, we observed that the compound helped these cells move toward beta-amyloid plaques and better contain the damage associated with the disease.”
The study also found that OLE increased Aβ chemotaxis and clearance in cultured microglia. In neuronal cultures exposed to Alzheimer’s-related stressors, OLE enhanced cell survival, indicating that the molecule may have direct neuroprotective effects in addition to its effects on immune cells.
The team believes OLE may function as a disease-modifying therapy by altering microglial behavior and reducing amyloid-associated damage, but because OLE was administered systemically in their experiments, more work is needed to determine whether its primary effects occur in microglia or whether it acts independently on multiple cell types. They also plan to investigate whether other N-acyl amino acids have therapeutic potential and whether OLE can influence tau pathology and neurodegeneration.
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