Roberson ED, Scearce-Levie K, Palop JJ, Yan F, Cheng IH, Wu T, Gerstein H, Yu GQ, Mucke L. Reducing endogenous tau ameliorates amyloid beta-induced deficits in an Alzheimer's disease mouse model. Science. 2007 May 4;316(5825):750-4. PubMed.

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  1. The paper supports the notion that tauopathy plays a major role in AD pathogenesis.

    View all comments by Takaomi Saido

  2. This is a remarkable report. It addresses key aspects of the underlying mechanisms of AD and has significant implications for AD drug discovery. Guided in large part by the amyloid cascade hypothesis, most potential treatments for AD target one or more aspects of Aβ amyloidosis, by reversing amyloid plaques, reducing levels or Aβ, inhibiting Aβ fibrillization, or promoting clearance of toxic Aβ fibrils or oligomeric species of Aβ. The microtubule-associated protein tau also is implicated in mechanisms of AD, but tau has often been considered to be downstream of the toxic effects of Aβ. However, the data presented here by Roberson et al. show that reducing endogenous levels of tau prevented behavioral deficits in transgenic mice expressing human amyloid precursor protein without altering their high levels of brain Aβ. Significantly, these data suggest that by reducing levels of brain tau, it may be possible to block Aβ-mediated neuronal dysfunction and neurodegeneration. The authors suggest this strategy may represent a novel approach to developing better therapies for AD and related disorders known as tauopathies.

    Since most insights into tauopathies have come from studies of AD, there is extensive literature on tau pathologies in AD. But a substantial amount of data also has come from studies of related tauopathies, wherein tau pathology is the critical underlying abnormality that links all of these disorders to a shared mechanism of neurodegeneration. For example, when tau becomes hyperphosphorylated, it forms amyloid filaments that aggregate to form neurofibrillary tangles (NFTs). As a result, this leaves less tau available to stabilize microtubules (MTs), and when MTs are destabilized, this compromises intraneuronal transport leading to neurodegeneration. Thus, several types of tau-focused interventions are being developed, including some that are directed at abrogating tau fibrillization or hyperphosphorylation, and others that are designed to stabilize MTs by compensating for the sequestration of tau in NFTs (Schenk et al.; Skovronsky et al.). However, while it may be desirable to suppress mutant forms of tau in hereditary tauopathies or in tauopathies with an abnormal ratio of 3- versus 4-repeat tau isoforms, reducing tau levels to the extent that MT stability is compromised is likely to have long-term deleterious effects. For example, the report by Ikegami et al. on tau knockout mice demonstrated that these tau-deficient mice develop cognitive and motor abnormalities with age. This signifies that reducing tau levels may have negative consequences. However, there are few studies examining the behavioral and CNS consequences of reducing tau levels over the lifespan, and hopefully the studies by Roberson et al. make it clear that far more research is needed on this topic if we are to exploit their findings for therapeutic benefit of patients with AD or a related tauopathy.

    References:

    Ikegami S, Harada A, Hirokawa N. Muscle weakness, hyperactivity, and impairment in fear conditioning in tau-deficient mice. Neurosci Lett. 2000 Feb 4;279(3):129-32. PubMed.

    Schenk D, Carrillo MC, Trojanowski JQ. Cytoskeletal modulators and pleiotropic strategies for Alzheimer drug discovery. Alzheimers Dement. 2006 Oct;2(4):275-81. PubMed.

    Skovronsky DM, Lee VM, Trojanowski JQ. Neurodegenerative diseases: new concepts of pathogenesis and their therapeutic implications. Annu Rev Pathol. 2006;1:151-70. PubMed.

    View all comments by John Trojanowski

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