New Study May Lead to New Strategies for Treatment of Alzheimer’s

September 27, 2010

tau proteins A new study uncovers a protein modification that may contribute to the formation of neuron-damaging neurofibrillary tangles in the human brain. The research may lead to new strategies for treatment of neurodegenerative diseases that result from pathological aggregation of tau protein.

Tau protein is common in the central nervous system where it helps to stabilize microtubules that form the neuronal cytoskeleton. Tau mutations have been linked with dementia and Alzheimer’s disease, and accumulation of phosphorylated tau protein (p-tau) has been implicated in neurodegeneration. However, the molecular mechanisms that underlie abnormal tau aggregation have not been elucidated.

“We know that an enzyme called SIRT1 is reduced in the Alzheimer’s disease brain and that this reduction correlates with the accumulation of p-tau. Further, overexpression of SIRT1 protects against neuronal loss in a mouse model of Alzheimer’s disease,” explains senior study author, Dr. Li Gan. “However, how SIRT1 protects against tau-mediated neurodegeneration is not clear.”

SIRT1 is a deacetylase, an enzyme that removes acetyl groups from proteins. Like phosphorylation, acetylation regulates many different cellular functions, including cytoskeleton dynamics. “To determine whether tau is acetylated and whether tau acetylation contributes to tau accumulation, we investigated tau acetylation in neurons, mouse models of tauopathy, and Alzheimer’s disease brains,” says Dr. Gan.

Dr. Gan’s group found that tau acetylation prevents degradation of p-tau, and patients at early and moderate stages of tauopathy exhibited elevated tau acetylation. The researchers went on to show that inhibiting SIRT1 increased levels of acetylated and pathogenic tau while a small molecule inhibitor of p300, an enzyme known to attach acetyl groups to proteins, promoted tau deacetylation and eliminated p-tau associated with pathological conditions.

While the link between tau acetylation and tau phosphorylation is not known, the results provide new insight into tau-mediated neuropathology. “Our findings support the model that the abnormally elevated acetylation at an early stage of the disease could block clearance of p-tau from neurons, leading to its accumulation,” concludes Dr. Gan. “Our observation that p300 diminished tau acetylation and effectively eliminated p-tau supports the idea that interfering with tau acetylation may be a new approach for reducing tau-related pathology.”

1. Li Gan, et al. Acetylation of Tau Inhibits Its Degradation and Contributes to Tauopathy. Neuron, 2010; 67 (6): 953-966 DOI: 10.1016/j.neuron.2010.08.044

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  1. Rovshan Ismailov MD MPH PhD

    March 22, 2011 at 7:39 am

    The accumulation of tau proteins – what’s the mechanism?

    With the appearance of the “hypoperfusion” theory as well as findings from numerous population-based studies linking Alzheimer’s disease to “vascular” disorders (i.e. hypertension, atherosclerosis etc.)[1,2], it became evident that the important task for understanding Alzheimer’s disease is to thoroughly examine local fluid dynamics. Such consideration of regional brain extravascular extracellular fluid dynamics is important in light of the fact that certain substances such as phosphorylated tau protein can accumulate causing degradation of certain cellular components thus playing an important role in the pathogenesis of Alzheimer’s disease[4,5].

    Such mechanism proposes that the regional brain extravascular extracellular fluid gets moved due to the cyclic changes in the vessel wall deformation, a sort of a “deformation pump”[3]. The operating principle of the “deformation pump” is in the cyclic creation of the boundary layer and in its separation. Thus the movement of the regional brain extravascular extracellular fluid happens as a result of the appearance and separation of the boundary layer at the close proximity to the vascular wall. The obvious implication of this mechanism is the primary involvement of cardiovascular system in the development of Alzheimer’s disease.

    Rovshan M Ismailov, M.D., M.P.H., Ph.D.


    [1] de la Torre JC. Impaired brain microcirculation may trigger Alzheimer’s disease. Neurosci Biobehav Rev 1994; 18(3):397-401.
    [2] de la Torre JC. Cerebral hypoperfusion, capillary degeneration, and development of Alzheimer disease. Alzheimer Dis Assoc Disord 2000; 14 Suppl 1:S72-81.
    [3] Ismailov RM. New insights into the mechanism of Alzheimer’s disease: A multidisciplinary approach . edn. Amazon Kindle, 2010.
    [4] Mattson MP. Calcium as sculptor and destroyer of neural circuitry. Exp Gerontol 1992; 27(1):29-49.
    [5] Khachaturian ZS. The role of calcium regulation in brain aging: reexamination of a hypothesis. Aging (Milano) 1989; 1(1):17-34.

  2. Maria bars

    April 3, 2015 at 4:39 am

    Could you please advise me how to inhibit and disassemble genetic tau aggregation. I suffer from a rare genetic tau aggregation illness called pallido ponto nigral degeneration. A response will truly be appreciated.

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