Scientists from the Lewis Katz School of Medicine at Temple University say they have shown for the first time that a molecule known as VPS35 clears the brain of the potentially harmful tau protein, which otherwise accumulates and contributes to neurodegenerative disorders, including Alzheimer’s disease. The team’s study (“VPS35 regulates tau phosphorylation and neuropathology in tauopathy”) appears in Molecular Psychiatry.
“A major part of what VPS35 does is to sort out and transport dysfunctional proteins to degradation sites,” explained senior investigator Domenico Praticò, MD, Scott Richards North Star Foundation Chair for Alzheimer’s Research, professor in the departments of pharmacology and microbiology, and director of the Alzheimer’s Center at Temple at the Lewis Katz School of Medicine (LKSOM).
The buildup of defective proteins in neurons is a feature shared by Alzheimer’s disease, Parkinson’s disease, and several other neurodegenerative conditions. Tau is one of the major proteins to amass in the brain and cause damage in these diseases, creating a condition described as tauopathy.
Previous work by other researchers had shown that the function of VPS35 is altered in Alzheimer’s disease and that VPS35 activity is reduced in the brains of Alzheimer’s patients. The relationship between VPS35 activity and tau accumulation was largely unexplored.
“We asked specifically whether the VPS35 system is important for clearing defective tau proteins,” Praticò said. To answer this question, his team of researchers examined brain tissue from patients with either progressive supra-nuclear palsy (PSP) or Picks’ disease. Unlike Alzheimer’s disease, in which tau accumulation is secondary to that of beta-amyloid, in PSP and Picks’ disease tau is the only protein to form deposits in the brain.
Analyses revealed that the brains of PSP and Pick’s disease patients had VPS35 levels that were 50% lower than those of control subjects. When the researchers deliberately altered VPS35 levels in individual tauopathy-affected neurons in vitro, they discovered that they could directly control tau accumulation, for the first time implicating VPS35 in tauopathy. The VPS35-dependent effect on tau was mediated by the activity of cathepsin D, an enzyme that specializes in protein degradation.
“The vacuolar protein sorting 35 (VPS35) is a major component of the retromer recognition core complex which regulates intracellular protein sorting and trafficking. Deficiency in VPS35 by altering APP/Aβ metabolism has been linked to late-onset Alzheimer’s disease. Here we report that VPS35 is significantly reduced in PSP and Picks’ disease, two distinct primary tauopathies. In vitro studies show that overexpression of VPS35 leads to a reduction of pathological tau in neuronal cells, whereas genetic silencing of VPS35 results in its accumulation,” the investigators wrote.
“Mechanistically the availability of active cathepsin D mediates the effect of VPS35 on pathological tau accumulation. Moreover, in a relevant transgenic mouse model of tauopathy, down-regulation of VPS35 results in an exacerbation of motor and learning impairments as well as accumulation of pathological tau and loss of synaptic integrity. Taken together, our data identify VPS35 as a novel critical player in tau metabolism and neuropathology, and a new therapeutic target for human tauopathies.”
“When tau lingers in cells, it is very bad for synapses, the places where neurons meet and exchange signals,” explained Praticò. “In the animals we studied, there was a 40–50% loss in synaptic connectivity when VPS35 activity was reduced, which led to the types of cognitive and motor deterioration, including losses in memory and learning ability, seen in human tauopathy patients.”
The discovery of the involvement of cathepsin D shed additional light on the relationship between VPS35 and tau. “Without VPS35, cathepsin D does not degrade tau, leaving tau to build up in the brain,” Praticò said.
Praticò’s team plans next to investigate the possibility of using a drug to put VPS35 back to work in the context of neurodegenerative disease. “The approach would be unique. Instead of targeting an enzyme, as other small molecules have been developed to do, we would be targeting an actual mechanism, which should be more viable,” he said.
