A “chaperone” molecule that slows the formation of
certain proteins reversed disease signs, including memory impairment, in a
mouse model of Alzheimer’s disease, according to a study from researchers at
the Perelman School of Medicine at the University of Pennsylvania.
In the study, published in Aging Biology, researchers
examined the effects of a compound called 4-phenylbutyrate (PBA), a fatty-acid
molecule known to work as a “chemical chaperone” that inhibits protein
accumulation. In mice that model Alzheimer’s disease, injections of PBA helped
to restore signs of normal proteostasis (the protein regulation process) in the
animals’ brains while also dramatically improving their performance on a
standard memory test, even when administered late in the disease course.
“By generally improving neuronal and cellular health, we
can mitigate or delay disease progression,” said study senior author Nirinjini
Naidoo, PhD, a research associate professor of Sleep Medicine. “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.”
Previously, researchers found that PBA treatment improved
sleep quality and cognitive test performance—and helped normalize
proteostasis—in mice that model ordinary human brain aging. For the new study,
they investigated PBA’s effects in mice that model Alzheimer’s disease. These
mice, known as APPNL-G-F mice, accumulate abnormal protein aggregates in their
brains, lose many of the synapses that connect their brain cells, and develop
severe memory impairment—much like people with Alzheimer’s.
First, the team showed that these mice do indeed have
signs of dysfunctional proteostasis mechanisms—including a chronically
activated process called the unfolded protein response—and relatively low
levels of a natural aggregate-preventing “chaperone” protein called binding
immunoglobulin protein (BiP) or Hspa5.
Next, graduate student Jennifer Hafycz treated the mice,
starting early in life, with PBA, finding that the treatment helped restore
signs of normal proteostasis in key memory-related brain regions in the mice.
The treatment also restored the mice’s ability—which was otherwise abolished—to
discriminate between moved and unmoved objects on a standard memory test called
the Spatial Object Recognition test.
The team discovered that they could achieve similar
effects, including the reversal of memory deficits, even when they treated the
mice starting in middle age.
Both early-life and middle-age treatment showed signs of
inhibiting the process that forms the most prominent protein aggregates in
Alzheimer’s, known as amyloid beta plaques. For the later treatment, not only
the underlying process but also the amyloid plaque numbers themselves were
reduced.
As a potential Alzheimer’s treatment, PBA has the
advantage that it can cross easily from the bloodstream into the brain and is
already approved by the Food and Drug Administration for treating an unrelated
metabolic disorder.
While more research is needed, particularly in human
trials, this represents a significant step forward in the search for effective
treatments for this challenging disease.
Sources and Additional Information:
https://knowridge.com/2023/12/new-hope-in-alzheimers-treatment/
