An interesting paper... it would be good to know, though, whether tau was "essential" to other forms of induced neurotoxicity.

View all comments by John Hardy

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

View all comments by Takaomi Saido

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...  Read more

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. Abstract

Schenk, D., Carrillo, M.C., and Trojanowski, J.Q. Perspective: Cytoskeletal modulators and pleiotropic strategies for Alzheimer drug discovery. Alzheimer’s & Dementia: J. Alzheimer’s Assoc., 2:275-281, 2006.

Skovronsky DM., Lee VM-Y, Trojanowski JQ. Neurodegenerative diseases: New concepts of pathogenesis and their therapeutic implications. Annu Rev Pathol Mech Dis 2006; 1:151-170.

View all comments by John Trojanowski

Nicholson and Ferreira’s new findings provide an important advance in our understanding of why high cholesterol levels may increase the vulnerability of neurons to dysfunction and death in Alzheimer disease. Previous studies in my laboratory and other laboratories had shown that Aβ can damage neurons by a mechanism involving membrane-associated oxidative stress and consequent perturbation of membrane proteins involved in the maintenance of cellular calcium homeostasis. As a result, calcium levels inside the neurons may rise excessively, resulting in damage to synapses and cell death. In addition, Ferreira and colleagues had previously provided evidence that the microtubule-associated protein tau is cleaved by calcium-activated proteases to generate a 17 kDa tau fragment that may itself adversely affect neurons.

In the present study, Nicholson and Ferreira manipulated and measured levels of cholesterol, tau proteolysis, and intracellular calcium levels in cultured hippocampal neurons exposed to Aβ. They found that when cholesterol levels are elevated, the neurons are more...  Read more

Nicholson and Ferreira’s new findings provide an important advance in our understanding of why high cholesterol levels may increase the vulnerability of neurons to dysfunction and death in Alzheimer disease. Previous studies in my laboratory and other laboratories had shown that Aβ can damage neurons by a mechanism involving membrane-associated oxidative stress and consequent perturbation of membrane proteins involved in the maintenance of cellular calcium homeostasis. As a result, calcium levels inside the neurons may rise excessively, resulting in damage to synapses and cell death. In addition, Ferreira and colleagues had previously provided evidence that the microtubule-associated protein tau is cleaved by calcium-activated proteases to generate a 17 kDa tau fragment that may itself adversely affect neurons.

In the present study, Nicholson and Ferreira manipulated and measured levels of cholesterol, tau proteolysis, and intracellular calcium levels in cultured hippocampal neurons exposed to Aβ. They found that when cholesterol levels are elevated, the neurons are more vulnerable to Aβ toxicity, and the increased vulnerability is associated with increased intracellular calcium levels and increased production of the 17 kDa tau fragment. Our previous findings indicated that the increased oxidative stress that occurs during aging and AD may itself perturb membrane cholesterol and sphingomyelin metabolism (Cutler et al., 2004). Collectively, the available data suggest that a self-propagating neurodegenerative cascade may occur in AD in which oxidative stress perturbs lipid metabolism, resulting in impaired calcium regulation and pathological changes in tau which, in turn, exacerbate oxidative stress and further disrupt cellular calcium homeostasis. Lowering cholesterol levels through dietary modifications, exercise, and statins may, therefore, stabilize cellular calcium homeostasis and so protect neurons against dysfunction and degeneration in aging and AD.

View all comments by Mark Mattson