Summary: Researchers identify a fragmented, caspase-6–cleaved form of tau that accumulates in neurons in Alzheimer’s disease and could improve diagnosis and provide a new therapeutic target.
Source: UCSF
Researchers at the University of California, San Francisco report that a previously underappreciated form of the tau protein—tau that has been truncated into fragments—is abundant in the brains of people with Alzheimer’s disease and may be an important driver of neurodegeneration. This finding suggests new opportunities for more specific diagnostics and for drug development aimed at slowing or preventing disease progression.
The study shows that tau fragments produced when the enzyme caspase-6 cleaves the tau protein accumulate in many neurons within Alzheimer’s pathology. This truncated tau (tr-tau) is distinct from the well-studied hyperphosphorylated tau (phospho-tau or p-tau) that forms the classic neurofibrillary tangles. Importantly, a substantial fraction of neurons with truncated tau do not show p-tau on standard tests, meaning that conventional biomarkers may miss a large portion of tau-driven neuronal injury.
Because caspase-6–generated tau fragments appear common in Alzheimer’s and in Pick’s disease but rare in other tau-related dementias, measuring these specific fragments in cerebrospinal fluid (CSF) could improve diagnostic accuracy and allow better disease staging. The fragments—and the caspase-6 enzyme that generates them—also present therapeutic targets. Researchers note that drug-like inhibitors of caspase-6 are already in development, raising the possibility of repurposing or adapting these agents for Alzheimer’s.
“This work highlights a pathogenic process in Alzheimer’s that has not received enough attention,” said neuropathologist Lea T. Grinberg, MD, PhD, who co-led the study. Grinberg and colleagues found that a very large number of neurons within tau-laden tangles contain truncated tau, and experimental data indicate this form contributes substantially to neurodegeneration and cognitive decline in Alzheimer’s disease.
Neurons “Not on the Radar”
Previous research focused largely on phospho-tau, which forms the neurofibrillary tangles characteristic of Alzheimer’s. Clinical efforts to target phospho-tau have had limited success to date. This new work shows that truncated tau produced by caspase-6 has a separate and significant role in Alzheimer’s and in Pick’s disease (a primary tauopathy), while it is marginal in four-repeat (4R) tauopathies.
The team used donated brain tissue from UCSF’s Neurodegenerative Disease Brain Bank to examine tau pathology in samples from 37 individuals. They discovered that some neurons contained both truncated and phosphorylated tau, while many others contained only truncated tau. Because most diagnostic panels target p-tau, neurons harboring tr-tau alone can remain undetected, obscuring the true extent of tau-related damage.
Furthermore, the distinctive prevalence of tr-tau in Alzheimer’s and Pick’s disease—but not in most other tauopathies—suggests that assays for these fragments could help clinicians distinguish between different forms of dementia during life, a diagnostic challenge that currently lacks reliable solutions.
Leveraging Existing Drug Development
Michelle Arkin, PhD, another study co-leader and chair of Pharmaceutical Chemistry, led the development of monoclonal antibodies selective for the neoepitopes generated when caspase-6 cleaves tau. These tools allowed precise detection and quantification of tr-tau species. Building on those findings, Arkin and colleagues including pharmaceutical chemist Adam Renslo, PhD, are developing drug-like inhibitors designed to prevent caspase-6 from producing the toxic tau fragments.
Blocking caspase-6 activity could reduce the generation of tr-tau and potentially slow tau-driven neuronal loss. The authors suggest that early modulation of caspase-6 may be a promising therapeutic strategy for Alzheimer’s disease and Pick’s disease, although it is unlikely to be effective in 4R tauopathies where caspase-6 activation and tr-tau are minimal.
In addition to therapeutic implications, the disproportionate burden of tr-tau in Alzheimer’s supports the development of biofluid biomarkers that specifically detect caspase-6–cleaved tau to improve clinical diagnosis and to identify patients most likely to benefit from caspase-6–targeted interventions.
Authors and contributors: The study was co-led by Lea T. Grinberg, MD, PhD and Michelle Arkin, PhD. Additional UCSF contributors include Panos Theofilas, PhD; Antonia Piergies; Ian Oh; Yoo Bin Lee; Song Hua Li; Felipe Pereira, PhD; Cathrine Petersen; Alexander Ehrenberg; Rana Eser; Andrew Ambrose, PhD; Salvatore Spina, MD, PhD; William Seeley, MD; and Bruce Miller, MD.
Funding: The research was supported by multiple National Institutes of Health grants, the Alzheimer’s Association, UCSF’s Catalyst program, and philanthropic contributions.
About this Alzheimer’s disease research news
Author: Robin Marks
Source: UCSF
Contact: Robin Marks – UCSF
Image: The image is in the public domain
Original research: Open access. Title: “Caspase-6-cleaved tau is relevant in Alzheimer’s disease and marginal in four-repeat tauopathies: Diagnostic and therapeutic implications” by Lea T. Grinberg et al., published in Neuropathology and Applied Neurobiology.
Abstract
Title: Caspase-6-cleaved tau is relevant in Alzheimer’s disease and marginal in four-repeat tauopathies: Diagnostic and therapeutic implications
Aim
The study examined whether tau truncation (tr-tau) produced by active caspase-6 (aCasp-6) generates fragments that are toxic, and how aCasp-6, various tr-tau species, and hyperphosphorylated tau (p-tau) relate to each other in brains affected by Alzheimer’s disease and other tauopathies.
Methods
Researchers produced two monoclonal antibodies targeting neoepitopes created by caspase-6 cleavage (sites D402 and D13). Using multiplex immunofluorescence, they quantified neuronal and astroglial burdens of aCasp-6, tr-tau, and p-tau and assessed their co-occurrence across healthy controls, Alzheimer’s disease, and primary tauopathies.
Results
Caspase-6 activation was strongest in Alzheimer’s disease and Pick’s disease but nearly absent in four-repeat (4R) tauopathies. Tr-tau burden in neurons was much higher in Alzheimer’s and Pick’s disease compared with 4R tauopathies, and this burden remained disproportionately high when normalized to p-tau pathology. Tr-tau associated with astroglia was detected at low levels in 4R tauopathies. Unexpectedly, about half of tr-tau–positive neurons in Alzheimer’s and Pick’s disease did not show p-tau aggregates, a result corroborated using multiple p-tau antibodies.
Conclusions
Modulating caspase-6 early to reduce tr-tau pathology represents a promising therapeutic approach for Alzheimer’s disease and Pick’s disease, but is unlikely to benefit 4R tauopathies. Because many tr-tau–positive neurons lack p-tau, relying solely on p-tau markers may underestimate the extent of tau pathology. Developing therapies and biofluid biomarkers that target tr-tau could be essential for detecting and treating Alzheimer’s disease and differentiating it from other tauopathies at the patient level.