Drug 'chaperone' fends off Alzheimer's in mice by preventing toxic protein clumping

Temple University researchers are targeting VPS35, a molecule that’s key to the ability of brain cells to remove toxic proteins in Alzheimer's disease. (VSRao/Pixabay)

Alzheimer’s disease has long been associated with the harmful proteins amyloid beta and tau. They clump up in the brain, disrupting neurons and causing memory loss and other symptoms. Researchers at Temple University’s Lewis Katz School of Medicine say they’ve found a new way to prevent amyloid beta and tau from building up in the brain.

The Temple team is studying a drug that helps brain cells recognize defective proteins so they can stabilize or remove them altogether before they form toxic clumps. In mouse models of Alzheimer’s, animals who received the drug prior to developing symptoms experienced decreases in tau tangles and amyloid plaques, the researchers reported in the journal Molecular Neurodegeneration.

The researchers refer to their drug as a “chaperone,” because it’s designed to boost levels of a molecule that’s key to cells’ ability to sort and move proteins. That molecule, VPS35, separates dysfunctional proteins and moves them out of cellular compartments called endosomes so they can be discarded.


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Previous research from Temple revealed that levels of VPS35 fall in Alzheimer’s disease. They linked that decline with the formation of tau tangles inside of neurons and amyloid plaques outside of them.

The drug chaperone, dubbed TPT-172, replenished levels of VPS35 in the mouse models. That restored the functioning of synapses, which are the places neurons connect and share information. The mice treated with the drug showed improvements in memory and behavior as compared to animals that were also destined to develop Alzheimer’s but were given no treatment. The researchers reported that the Alzheimer’s models that received TPT-172 behaved like normal, wild mice.

RELATED: Small Alzheimer's hopeful biotech nabs $15M series B for metabolic drug approach

Drugs targeting amyloid in Alzheimer’s have so far proven disappointing, but combating toxic brain plaques is still an approach several biotechs are pursuing. Among them is T3D Therapeutics, which raised $15 million in a series B round late last year to develop a drug that addresses protein misfolding in the brain by correcting improper glucose and fat metabolism.

In December, Biogen paid $45 million to license an antisense treatment from Ionis that’s designed to reduce the production of tau protein. That drug is currently in phase 1 testing. And Biogen hasn’t given up on its amyloid-targeted drug aducanumab, even though an initial analysis of the phase 3 program questioned whether it would ultimately succeed.

Unlike other investigational therapies that are designed to block proteins, TPT-172 targets a cellular mechanism, which could help limit the potential side effects, argued Domenico Praticò, M.D., professor and director of Temple’s Alzheimer’s Center, in a statement. That adds “to the appeal of pursuing pharmacological chaperone drugs as novel Alzheimer's treatments,” he said.

The next step for Praticò’s team is to test TPT-17 in older mice. “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 said.

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