Summary: VPS35 is a newly identified key regulator of tau metabolism and plays a critical role in the pathology of neurodegenerative diseases.
Source: Temple University Health System
Overview: A protein called VPS35 acts like a cellular sorting machine, identifying and directing defective proteins to degradation pathways in neurons. New research from the Lewis Katz School of Medicine at Temple University reveals that VPS35 helps clear the brain of tau, a protein that, when it accumulates, drives neurodegenerative disorders such as Alzheimer’s disease and primary tauopathies. The study highlights VPS35 as an important factor in maintaining neuronal health and suggests it may be a promising therapeutic target.
The findings were published online July 9 in the journal Molecular Psychiatry.
Domenico Praticò, MD, senior investigator and Director of the Alzheimer’s Center at the Lewis Katz School of Medicine, explains that VPS35 is a critical component of the retromer complex responsible for sorting and transporting dysfunctional proteins to cellular degradation sites. When this mechanism falters, harmful proteins can accumulate and damage neurons.
Tau accumulation, or tauopathy, is a hallmark of several neurodegenerative diseases, including Alzheimer’s disease and distinct primary tauopathies. While previous studies had linked altered VPS35 function to Alzheimer’s disease and reported reduced VPS35 activity in Alzheimer’s patient brains, the direct relationship between VPS35 and tau accumulation had not been fully explored.
To investigate this link, the research team examined brain tissue from patients diagnosed with progressive supranuclear palsy (PSP) and Pick’s disease—conditions in which tau is the primary protein forming deposits, unlike Alzheimer’s where beta-amyloid also plays a leading role. Analyses showed VPS35 levels were roughly 50 percent lower in PSP and Pick’s disease brains compared with control subjects.
In laboratory experiments using cultured neurons affected by tauopathy, the researchers manipulated VPS35 levels and observed corresponding changes in tau accumulation. Increasing VPS35 reduced pathological tau, while silencing VPS35 caused tau to build up. These results provide direct evidence that VPS35 regulates tau levels in neurons.
Mechanistic studies identified cathepsin D, a lysosomal enzyme that degrades proteins, as a mediator of this VPS35 effect. When VPS35 is reduced, active cathepsin D availability declines, impairing tau degradation and allowing pathological tau to accumulate.
Complementing the cellular work, the team conducted experiments in a transgenic mouse model of tauopathy. Animals with VPS35 downregulation exhibited worsened learning and memory deficits, impaired motor function, and significant loss of synaptic integrity. According to the investigators, reduced VPS35 activity produced a 40 to 50 percent decrease in synaptic connectivity in these animals, consistent with the cognitive and motor decline observed in human tauopathy patients.
These results indicate that preserving or restoring VPS35 function could protect synapses and neuronal communication by promoting cathepsin D–dependent clearance of pathological tau. Dr. Praticò and colleagues propose that therapeutic strategies aimed at reactivating VPS35 may offer a new approach distinct from traditional enzyme-targeting drugs. By targeting an underlying cellular mechanism—protein sorting and trafficking—rather than a single enzymatic step, such therapies could provide a broader and potentially more durable benefit in tauopathies.
The study team includes Alana N. Vagnozzi, Jian-Guo Li, Jin Chiu, and Rebecca Warfield from the Alzheimer’s Center and Department of Pharmacology at LKSOM, and Roshanak Razmpour and Servio H. Ramirez from the Department of Pathology and Laboratory Medicine at LKSOM.
Funding: This research was supported in part by National Institutes of Health grants AG055707 and AG056689.
Source:
Temple University Health System
Media Contact:
Jeremy Walter – Temple University Health System
Image Source:
The image is in the public domain.
Original Research: Closed access. Study title: “VPS35 regulates tau phosphorylation and neuropathology in tauopathy.” Authors: Alana N. Vagnozzi, Jian-Guo Li, Jin Chiu, Roshanak Razmpour, Rebecca Warfield, Servio H. Ramirez & Domenico Praticò. Published in Molecular Psychiatry. DOI: 10.1038/s41380-019-0453-x.
Abstract summary: VPS35 is a component of the retromer complex that governs intracellular protein sorting and trafficking. Deficiency in VPS35 has been connected to late-onset Alzheimer’s disease through altered APP/Aβ metabolism. This study reports a significant reduction of VPS35 in progressive supranuclear palsy and Pick’s disease. Overexpression of VPS35 in neuronal cells reduced pathological tau, while VPS35 silencing caused tau accumulation. The effect on tau is mediated by the availability of active cathepsin D. In a transgenic tauopathy mouse model, VPS35 down-regulation worsened motor and learning impairments, increased pathological tau accumulation, and reduced synaptic integrity. Together, these findings position VPS35 as a critical regulator of tau metabolism and a promising therapeutic target for human tauopathies.