A drug that boosts activity in the brain’s “garbage disposal” system can decrease levels of toxic proteins associated with Alzheimer’s disease and other neurodegenerative disorders and improve cognition in mice, a new study by neuroscientists at Columbia University Medical Center (CUMC) and New York State Psychiatric Institute (NYSPI) has found. The study was published today in the online edition of Nature Medicine.
“We have identified a new way to activate the brain’s garbage disposal system, and have shown that we can effectively use a drug to activate this system and slow down disease in a mouse model,” said study leader Karen E. Duff, PhD, professor of pathology and cell biology (in psychiatry and in the Taub Institute for Research on Alzheimer’s Disease and the Aging Brain) at CUMC and NYSPI. “This has the potential to open up new avenues of treatment for Alzheimer’s and many other neurodegenerative diseases.”
The drug used was rolipram, which causes nausea and thus is not a good drug for use in humans. However, similar drugs do not incur nausea as a side effect and can be potentially tested in clinical trials quickly.
Rolipram activates the brain’s garbage disposal system, eliminating excess Tau proteins (glowing red dots) associated with neurodegenerative diseases such as Alzheimer’
The ubiquitin proteasome system (UPS) degrades misfolded proteins including those implicated in neurodegenerative diseases. We investigated the effects of tau accumulation on proteasome function in a mouse model of tauopathy and in a cross to a UPS reporter mouse (line Ub-G76V-GFP). Accumulation of insoluble tau was associated with a decrease in the peptidase activity of brain 26S proteasomes, higher levels of ubiquitinated proteins and undegraded Ub-G76V-GFP. 26S proteasomes from mice with tauopathy were physically associated with tau and were less active in hydrolyzing ubiquitinated proteins, small peptides and ATP. 26S proteasomes from normal mice incubated with recombinant oligomers or fibrils also showed lower hydrolyzing capacity in the same assays, implicating tau as a proteotoxin. Administration of an agent that activates cAMP–protein kinase A (PKA) signaling led to attenuation of proteasome dysfunction, probably through proteasome subunit phosphorylation. In vivo, this led to lower levels of aggregated tau and improvements in cognitive performance.
Nature Medicine - Tau-driven 26S proteasome impairment and cognitive dysfunction can be prevented early in disease by activating cAMP-PKA signaling
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Reposted via Next Big Future
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