The study, conducted by scientists at the Lewis Katz School of Medicine at Temple University, is the first to show that a pharmacological chaperone drug can disrupt cellular processes that cause damage to the brain giving rise to Alzheimer's disease.

Alzheimer's disease is a common chronic neurodegenerative disorder characterized by memory impairments due to irreversible changes to neuronal cells, including the formation of amyloid plaques and neurofibrillary tangles. Amyloid beta (Aβ) represents peptides, approximately 36 to 43 amino acids in length, that are the main component of amyloid plaques. Neurofibrillary -- or tau -- tangles are aggregates of hyperphosphorylated tau proteins.

Cells are equipped with molecular machinery that allows them to sort misfolded proteins such as Aβs and tau tangles to prevent them from accumulating and causing damage. Vacuolar protein sorting-associated protein 35 (VPS35) belongs to a group of vacuolar protein sorting genes that encode a protein of the retromer complex and are involved in the retrograde transport of proteins from endosomes to the Golgi apparatus in cells. Retromer complex dysfunction is associated with several neurodegenerative conditions, such as Parkinson's disease and Alzheimer's disease.

Specifically, postmortem Alzheimer's brains show decreased VPS35 expression. One in vitro model showed that downregulation of VPS35 increases Aβ formation. Another found that knock-out mice (deletion of VPS35 genes) with brain amyloidosis that resembles Alzheimer's disease had higher Aβ formation and amyloid peptides, cognitive impairments and synaptic dysfunction. A previous study conducted by the researchers demonstrated that the addition of VPS35 in transgenic mice reversed Alzheimer's symptoms including increased long-term memory, lower Aβ levels, and decreased tau formation.

In this study, the scientists explored if a pharmacological chaperone, Tpt-172, could prevent memory loss, Aβ deposits, and tau tangles in mice prone to develop Alzheimer's disease. Here, the pharmacological chaperone acts as a protein chaperone containing small molecules that serve a molecular scaffolding to cause misfolded proteins to fold and route correctly within the cell.

They found that chronic administration of the pharmacological chaperone via upregulation of VPS35 effectively prevented mice from developing the symptoms of Alzheimer's disease.

Dr. Domenico Praticò, Temple University Health System.

"Our chaperone drug specifically restored levels of a sorting molecule known as VPS35, which helps move proteins out of endosomes, compartments inside cells where proteins are sorted for degradation," explained senior author Dr. Domenico Praticò.

The administration of the pharmacological chaperone had no effect on the general health of the mice, and they found that mice treated with the chaperone had significant improvement in memory. Moreover, the research confirmed with a western blot and a variety of immunoassays that VPS35 was increased in mice treated with the chaperone.

The upregulation of VPS35 due to chaperone treatment resulted in restoration of retromer complex function and reduction in Aβ formation and tau phosphorylation that was confirmed with radioimmunoprecipitation assay-soluble and formic acid-extractable levels and western blot analysis, respectively.

Lastly, the team found that treated mice had higher levels of synaptophysin, a marker for healthy synaptic terminals, and lower levels of neuroinflammation according to biochemical and immunohistochemical analysis of biomarkers in neuronal cells.

"Relative to other therapies under development for Alzheimer's disease, pharmacological chaperones are inexpensive, and some of these drugs have already been approved for the treatment of other diseases," Praticò said. "Additionally, these drugs do not block an enzyme or a receptor but target a cellular mechanism, which means that there is much lower potential for side effects. All these factors add to the appeal of pursuing pharmacological chaperone drugs as novel Alzheimer's treatments."

Because this study was conducted on young mice, Praticò suggests that the experiment should be repeated in older mice to determine the specific effects of the pharmacological chaperone.

"Because our most recent investigation was a preventative study, we want to know now whether this therapy could also work as a treatment for patients already diagnosed with Alzheimer's disease," he added.

*Dr. Praticò is the Scott Richards North Star Charitable Foundation Chair for Alzheimer's Research, professor in the departments of pharmacology and microbiology, and director of the Alzheimer's Center at Temple in the Lewis Katz School of Medicine.

Do you have a unique perspective on your research related to neurodegenerative disease research? Contact the editor today to learn more.