||Dr. Karen Duff’s recent lecture focused on the role of tangles in Alzheimer’s disease and on possible therapeutic interventions.
Accumulation of either substance, she said, has been shown in cell and animal models to lead to loss of synapses, degeneration of neurons and memory loss. However the identification of mutations that cause AD in genes contributing
to the amyloid pathway has driven the urge to understand how A-beta or amyloid accumulation
contributes to the disease and how it can be neutralized to attempt to prevent or reverse the disease.
Today, however, “the field is moving to tau,” which is normally a soluble microtubule-binding protein. In a misfolded conformation, tau turns bad guy, accumulating in brain cells and destroying
them. Once tau pathology begins to propagate
in certain brain areas, the plunge from mild cognitive impairment to full-blown AD is virtually
assured. In addition to AD, at least 30 different
dementia, including Parkinson’s disease, involve what Duff called “tauopathy.”
In her studies on AD, she and her colleagues are looking for possible therapeutic targets against pathways that lead to both plaques and tangles forming. They hypothesize that, in the late-onset or sporadic form of AD (as opposed to the hereditary form, which tends to manifest earlier
in life), both paths are activated; preventing one pathway may not prevent the devastating effects of the other unless the therapy is started before the disease has really taken hold. In support
of this, human clinical trials have shown that immunotherapy to remove plaque amyloid only had limited success in preventing further decline in the patients and patients still died with end-stage AD, which included devastating tangle pathology.
|Once tau pathology begins to propagate in certain brain areas, the plunge from mild cognitive impairment to full-blown AD is virtually assured.
Duff said that although several approaches may be effective against both plaque (or A-beta) pathology and tangles, there are not currently
enough being tested; strategies against tau tangles especially need to be researched. A potential vulnerability in brain cells includes degradation pathways and autophagy (literally “self-eating”) pathways, which drugs could theoretically
target as a way of spurring the removal
of damaged organelles or abnormal proteins such as amyloid or tangle-type tau. Her lab’s recent work using a drug called trehalose that targets autophagy reduced levels of the dangerous
form of tau in a mouse model of disease; others have shown similar drugs can remove amyloid and even proteins causing Parkinson’s and Huntington’s disease. Targeting autophagy may eventually prove helpful as a therapy for a range of neurodegenerative diseases or diseases such as AD where several different proteins can accumulate in the same brain.
Interestingly, a person can harbor both plaques and tangles and not have any disease at all. “A crucial thing is where they accumulate,” Duff noted. Her most recen t work aims to look at why certain areas of the brain are vulnerable to plaques and tangles and how we can prevent them from spreading to these sensitive areas.
In summary, Duff concluded:
- Tangle pathology correlates best with cognitive
decline in AD and it does not seem to be prevented in patients with reduced amyloid load following immunotherapy.
- Therapeutics against tau (tangles, precursors)
are likely to be necessary to reduce cognitive
decline/degeneration once the disease has started.
- Disease is likely to be well-advanced at the earliest stage currently diagnosed (MCI, or mild cognitive impairment).
- Therapeutic approaches that target more than one pathological entity (plaques, tangles, Lewy bodies) may be more efficacious for diseases
such as AD that have mixed pathology.
The full talk is available at http://videocast.nih.gov/Summary.asp?File=15982.