Chaperone Works to Lessen Alzheimer’s Symptoms and Toxic Protein Buildup, Mouse Study Says
A molecular chaperone called TPT-172 was able to prevent proteins linked to Alzheimer’s — including amyloid-beta and tau — from building up in the brain, improve memory and ease brain inflammation when tested in a mouse model of the disease.
Several studies have identified genes linked to cellular structures known as endosomes as susceptibility risk factors for Alzheimer’s onset.
Endosomes are small membrane-bound compartments that act like vehicles, moving proteins and molecules from one part of a cell to another.
These structures are important for the transport of amyloid precursor protein (APP) when it gets broken down into amyloid-beta, the molecule responsible for the buildup of toxic plaques in the brains of Alzheimer’s patients. If endosomes don’t work as intended, amyloid-beta levels rise, forming plaques that damage and kill neurons.
One protein that enables the correct functioning of the endosome is the vacuolar protein sorting 35 (VPS35). VPS35 is part of a group of proteins called the retromer complex system, which is responsible for moving proteins out of endosomes.
Compared to healthy individuals, Alzheimer’s patients are known to have lower levels of VPS35 in the brain, and in vitro (lab) studies have shown that these lower levels can increase the formation of amyloid-beta aggregates.
Researchers at Temple University in Philadelphia used a pharmacological chaperone, a small molecule that can enter cells and act as ‘scaffolding’ to support the structure of a particular protein, to stabilize VPS35. This chaperone, called TPT-172, prevents VPS35 from being broken down in the cell, so that a higher amount of the protein is available and the retromer complex system is able to form normally.
“We selected this drug since previously it was reported to stabilize VPS35 against thermal denaturation, and by doing so to up-regulate its levels and restore the function of the entire complex system,” the researchers wrote.
TPT-172 was tested in a mouse model of Alzheimer’s disease, and changes were compared to control mice who did not receive the treatment.
Mice were given TPT-172 every day in their drinking water for nine months. Relative to controls, animals treated with TPT-172 performed significantly better in the Y-maze test. This test assesses working memory in rodents, and better scores reflect memory improvements.
Treatment with TPT-172 also resulted in a significant increase in the levels of VPS35. The increased availability of VPS35 and formation of the retromer complex resulted in significantly lower levels of amyloid-beta in the brains of the treated mice, likely due to the regulation of APP — amyloid precursor protein — metabolism.
As in Alzheimer’s patients, the mouse model used in the study accumulates a toxic version of the tau protein, called phosphorylated tau, in the brain. Phosphorylated tau clumps together to form tangles that eventually result in the death of nerve cells.
Mice treated with TPT-172 had significantly lower amounts of phosphorylated tau in their brains compared to control mice. This was likely due to the presence of a working VPS35 and restoration of the retromer complex.
Another symptom of Alzheimer’s is the breakdown of synapses, the junctions between two nerve cells that allow them to communicate. Compared to untreated animals, TPT-172 treated mice had significantly higher amounts of a biomarker that indicated synapses were functioning correctly.
The treatment also lowered neuroinflammation, another important aspect associated with Alzheimer’s disease.
“Collectively, our findings further support the active role and direct impact that the retromer complex has on AD pathophysiology [disease manifestation] by modulating both APP and tau metabolism,” the researchers wrote.
Since it is possible to target VPS35 with a pharmacological chaperone like TPT-172, it “represents a novel and viable therapeutic approach against AD [Alzheimer’s disease],” they added.
“Pharmacological chaperones [such as TPT-172] are inexpensive, and some of these drugs have already been approved for the treatment of other diseases,” Domenico Praticò, PhD, director of the Alzheimer’s center at the Lewis Katz School of Medicine at Temple and the study’s senior author, said in a press release.
“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,” Praticò added.
Taken together, these factors suggest that pharmacological chaperones could become promising candidates for new Alzheimer’s treatments.