“Chemical chaperone” improves Alzheimer’s signs in early & late disease

A new study has found that treatment with a ‘chemical chaperone’ assists in reducing the accumulation of protein plaques and restores cognitive functioning in mouse models of Alzheimer’s disease. The findings could lead to novel treatments to help treat this debilitating disease.

Although the causes of Alzheimer’s disease (AD) pathology are not fully understood, the disease is characterized by two things: cognitive decline and accumulation of proteins in the brain, commonly seen as tau tangles or amyloid beta aggregations known as plaques. Maintaining protein homeostasis, or proteostasis, is critical for cell function and survival, so the aberrant aggregations seen in AD indicate an imbalance in proteostasis.

The protein aggregations common to AD also increase endoplasmic reticulum (ER) stress. The ER produces proteins for the rest of the cell to function, and stress occurs when proteins misfold and aggregate, activating the unfolded protein response (UPR), a protein quality control process designed to restore proteostasis. During this process, a natural aggregate-preventing ‘chaperone protein’, called binding immunoglobulin protein (BiP), is produced to assist with proper protein folding.

Researchers from the Perelman School of Medicine at the University of Pennsylvania (Penn) have discovered that supplementing BiP with another chemical chaperone inhibits protein accumulation and restores proteostasis and cognitive function in mouse models of AD.

“By generally improving neuronal and cellular health, we can mitigate or delay disease progression,” said Nirinjini Naidoo, corresponding author of the study. “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.”

From previous studies on mouse models of aging, the researchers knew that supplementing BiP levels with 4-phenylbutyrate (PBA), a chemical chaperone, improved sleep quality and cognitive test performance and helped normalize proteostasis. For the current study, they examined the effects of PBA in mice that model AD, with accumulations of abnormal protein aggregates in their brains.

First, they confirmed that the mice showed signs of dysfunctional proteostasis, including chronic UPR activity and low levels of BiP. Then they treated them with PBA and found that it helped restore signs of normal proteostasis in key memory-related regions of the brain. The treatment also restored the mice’s ability to discriminate between moved and unmoved objects on a standard memory test.

Similar effects were seen whether the mice were given PBA early or later in life. Both early-life and middle-age treatment showed signs of inhibiting the process that forms amyloid beta plaques.

“Altogether, our data demonstrate that disrupted proteostasis and chronic UPR activity play a key role in AD and that supplementing chaperone levels is sufficient to restore both proteostasis and cognition during early and late-stage intervention paradigms,” said the researchers.

The researchers say their findings could lead to novel treatments for Alzheimer’s. They are at an advantage as the FDA has already approved PBA as a treatment for genetic metabolic syndromes in children, sickle cell disease and thalassemia.

The study was published in the journal Aging Biology.

Source: Penn Medicine

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