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Vol. LXII, No. 16
NIH RECORD HOME NIH RECORD ARCHIVES NIH HOME PAGE August 6, 2010
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The Tao of Tau
Tangles, Not Plaques, a New Focus in Alzheimer’s Research
By Rich McManus

On the front page...

Mainstream research on Alzheimer’s disease may be giving short shrift to the tangles part of the two-fisted pathology that has for decades been a hallmark of the disease: the development of plaques and neurofibrillary tangles in the brains of AD patients.

It is the latter feature that intrigues researchers such as Dr. Karen Duff, professor of pathology and cell biology at Columbia University’s Taub Institute for Research on Alzheimer’s Disease and the New York State Psychiatric Institute. She presented a Wednesday Afternoon Lecture in Masur Auditorium on June 23.

In a 75-minute talk titled “It Takes Tau to Tangle: Plaques, Tangles and Neurodegenerative Disease,” Duff explained how scientists are “reconciling the contributions of amyloid plaques (or A-beta, a peptide that forms plaques) and tau,” a protein causing tangles.

Continued...

  Dr. Karen Duff’s recent lecture focused on the role of tangles in Alzheimer’s disease and on possible therapeutic interventions.  
  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. NIHRecord Icon

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