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New clues in the hunt for Alzheimer’s therapies

For decades, scientists have struggled to understand Alzheimer’s disease (AD), the most common form of dementia. Is it caused by clumps of beta-amyloid protein, or tangles of tau protein, damaging the brain? Or are these molecular trash heaps the consequence of something else gone awry?  

Absent answers to these questions, a cure can feel far off. But a multidisciplinary team of UCSF scientists has found that an understudied form of the tau protein—fragmented tau—is also abundant in deteriorating parts of the Alzheimer’s disease brain, providing promising new avenues for detecting and treating the condition. 

The research, published June 2 in Neuropathology and Applied Neurobiology, was co-led by the UCSF School of Pharmacy’s Michelle Arkin, PhD, chair of the Department of Pharmaceutical Chemistry, and Lea T. Grinberg, MD, PhD, faculty member in the School of Medicine. 

The team studied donated brain tissue from 37 patients thanks to UCSF’s Neurodegenerative Disease Brain Bank and uncovered neurons with fragmented tau in the AD brain that would’ve otherwise gone unnoticed. Up until this point, scientists were limited by tools that could only detect the full-length version of tau associated with AD, called phospho-tau.  

Moreover, while fragmented tau was found in brain tissue from patients with AD or another dementia, Pick’s disease, it was barely detectable in other dementias that involve tau protein, suggesting that fragmented tau could be used to differentiate among these related diseases. 

“By looking only at changes in phospho-tau, we’re missing a lot of the pathological process,” said Grinberg. 

The researchers hope these observations will lead to better detection methods or even an effective treatment for AD. Arkin, who developed the antibodies used to visualize tau fragments in the brain, is now working with pharmaceutical chemistry colleague Adam Renslo, PhD, to develop drugs to block the enzyme, caspase-6, responsible for chopping up tau protein.

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Overlooked Proteins May Be Key to Better Diagnosis of Alzheimer’s (UCSF News)

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About the School: The UCSF School of Pharmacy aims to solve the most pressing health care problems and strives to ensure that each patient receives the safest, most effective treatments. Our discoveries seed the development of novel therapies, and our researchers consistently lead the nation in NIH funding. The School’s doctor of pharmacy (PharmD) degree program, with its unique emphasis on scientific thinking, prepares students to be critical thinkers and leaders in their field.