Researchers from the Perelman School of Medicine at the University of Pennsylvania report that a protein “chaperone” molecule reversed Alzheimer’s disease (AD) signs and improved memory in a mouse model.
Reporting in the journal Aging Biology, the investigators examined the effect a fatty-acid molecule called 4-phenylbutyrate (PBA) which has been shown to inhibit the accumulation of proteins. When the mouse models received injections of PBA, it helps restore normal proteostasis—the process of protein regulation—in the animals’ brains and improved their performance on a standard memory test, even when PBA was given late in the course of disease progression.
Senior author Nirinjini Naidoo, PhD, a research associate professor of Sleep Medicine, UPenn noted that “By generally improving neuronal and cellular health, we can mitigate or delay disease progression. 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.”
The new research builds upon previous work by Naidoo and colleagues published last year in Aging Cell, which showed that PBA treatment improved sleep quality and cognitive test performance and normalized proteostasis in a mouse model of normal human brain aging. The new research used a model of AD known as APPNL-G-F mice whose brains accumulate abnormal protein aggregates and lose many of synapses between brain cells which leads to memory impairment similar to effects of disease progression of people with AD.
Mice used in the study exhibited signs of dysfunctional proteostasis mechanisms such as the chronically activated process known as the unfolded protein response along with low levels of the aggregate preventing chaperone protein called binding immunoglobulin protein (BiP) or Hspa5.
Using these mice, the investigators began treating them with PBA and found that treatment helped restore signs of normal proteostasis in memory-related regions in the brains of the mouse models. It also restored the ability of the mice, which had previously lost this ability, to discriminate between moved and unmoved objects on the Spatial Object Recognition test, a standard test that measures memory.
The tests showed that both early-life and middle-age treatments of PBA showed signs that it was inhibiting the formation of beta-amyloid plaques, proteins that are known to be a major component of disease progression in AD. The team noted that when PBA was provided later it reduced both the underlying biological process and the total number of beta-amyloid proteins present and reversed Alzheimer’s disease symptom progression.
“Encouragingly, even late-stage chaperone treatment improves cognition and proteostasis,” the researchers wrote. “Collectively, this work could provide valuable insight into the development of novel therapeutics for this debilitating and pervasive disease.”
The investigators further noted the potential of PBA as a treatment in AD is encouraging since it can easily cross the blood-brain barrier and it has already been approved by the FDA to treat urea cycle disorders, a rare genetic condition.
