According to a study from the Perelman School of Medicine at the University of Pennsylvania, a “chaperone” molecule that delays the synthesis of certain proteins restored illness indications, including memory impairment, in a mouse model of Alzheimer’s disease.
Researchers evaluated the effects of 4-phenylbutyrate (PBA), a fatty-acid molecule known to operate as a “chemical chaperone” that suppresses protein accumulation, in the study published in Aging Biology. Injections of PBA helped restore evidence of normal proteostasis (the protein regulation process) in the animals’ brains while also significantly enhancing their performance on a routine memory test, even when given late in the disease course.
“By generally improving neuronal and cellular health, we can mitigate or delay disease progression,” said Nirinjini Naidoo, PhD, a research associate professor of Sleep Medicine and study senior author. “In addition, reducing proteotoxicity—irreparable damage to the cell that is caused by an accumulation of impaired and misfolded proteins—can help improve some previously-lost brain functions.”
Alzheimer’s disease affects more than 6 million Americans, and up to 13.8 million could be diagnosed by 2060 if no medical advances to delay or cure the illness are made. Alzheimer’s disease, like other neurodegenerative illnesses, is characterized by the formation of protein aggregates in the brain, as well as the disruption of proteostasis.
Previously, researchers discovered that PBA treatment enhanced sleep quality and cognitive test performance in rats that mirror normal human brain aging, as well as helped regulate proteostasis. They explored PBA’s effects in mice that imitate Alzheimer’s disease for the current study. These mice, known as APPNL-G-F mice, experience significant memory impairment after accumulating aberrant protein aggregates in their brains, losing many of the synapses that connect their brain cells.
First, the researchers demonstrated that these mice have signs of dysfunctional proteostasis mechanisms, including a chronically activated process known as the unfolded protein response, as well as relatively low levels of a natural aggregate-preventing “chaperone” protein known as binding immunoglobulin protein (BiP) or Hspa5.
The mice were then treated with PBA by graduate student Jennifer Hafycz, who discovered that the medication helped restore evidence of normal proteostasis in critical memory-related brain regions in the mice. The medication also restored the mice’s capacity to discern between moved and immobile items on a typical memory test known as the Spatial Object Recognition test, which had previously been lost.
The researchers discovered that they could accomplish identical results, including memory deficit restoration, even when they began treating the mice in middle age.
Both early-life and middle-age treatment appeared to prevent the process that produces the most visible protein aggregation in Alzheimer’s disease, known as amyloid beta plaques. The latter treatment lowered not just the underlying mechanism but also the quantity of amyloid plaques.
PBA has the benefit of easily crossing from the bloodstream into the brain and is already licensed by the Food and Drug Administration for treating an unrelated metabolic problem as a potential Alzheimer’s treatment.
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