Researchers from the Perelman School of Medicine at the University of Pennsylvania have discovered promising results using a “chaperone” molecule called 4-phenylbutyrate (PBA) to counter Alzheimer's disease symptoms, including memory deficits, in a mouse model. Published in Aging Biology, the study underscores PBA's efficacy as a chemical chaperone, inhibiting harmful protein accumulation that contributes to the disease's progression.
Dr. Nirinjini Naidoo, the study's senior author and a research associate professor of Sleep Medicine, emphasized the potential of enhancing neuronal and cellular health to mitigate Alzheimer's progression. “Addressing proteotoxicity, the cellular damage caused by aberrant protein accumulation, offers a promising avenue to restore lost brain functions,” noted Dr. Naidoo.
Highlighting the urgency, Alzheimer's disease currently afflicts over 6 million Americans, with projections suggesting diagnoses could soar to 13.8 million by 2060 without significant therapeutic advancements. Characterized by detrimental protein aggregates and impaired proteostasis, Alzheimer's pathophysiology mirrors other neurodegenerative disorders.
The research team previously observed PBA's beneficial effects on sleep quality, cognitive performance, and proteostasis in aging mouse models. Extending this investigation to Alzheimer's disease models, specifically APPNL-G-F mice exhibiting pathological protein accumulations, synaptic loss, and memory deficits akin to human Alzheimer's patients, revealed compromised proteostasis mechanisms and diminished levels of the protective chaperone protein, BiP or Hspa5.
Graduate student Jennifer Hafycz's experiments demonstrated that PBA treatment, initiated either early or during middle age, revitalized proteostasis in crucial memory-associated brain regions. Remarkably, PBA administration reinstated the mice's cognitive ability to discern between relocated and stationary objects in the Spatial Object Recognition test.
Significantly, PBA treatment effectively curtailed the formation of amyloid beta plaques, hallmark protein aggregates in Alzheimer's pathology. When administered later in life, PBA not only attenuated amyloid beta plaque formation but also diminished existing plaque burdens, amplifying its therapeutic potential.
One of PBA's notable advantages as a prospective Alzheimer's treatment lies in its ability to traverse the blood-brain barrier efficiently. Moreover, its existing FDA approval for managing a distinct metabolic disorder expedites its transition to clinical trials, offering renewed hope in Alzheimer's therapeutic landscape.
Source: Perelman School of Medicine at the University of Pennsylvania