What Have We Learned from the Tau Hypothesis?

Abstract

Until the appearance of the Danger Signals Hypothesis on Alzheimer’s disease (AD), none of the hypotheses on its pathogenesis accounted coherently for the diversity of the earliest events that trigger neurodegeneration, and that eventually result in senile plaques (SP) and neurofibrillary tangles (NFTs). The original version of the most commonly held amyloid hypothesis rests on the concept that amyloid-β (Aβ)_1–42 self-polymerizes over many years to form SP, which then triggers the entire array of subsequent brain lesions. However, recent findings point to unpleated Aβ oligomers (ADDLs) as the major culprit for synaptic impairment, well before neuronal degeneration ensues. Amyloid deposits thus appear to be a rather late event in a long chain driving progressively more severe neuronal, glial and neuropil alterations. AD is a multifactorial disorder in that protein alterations, oxidative stress, neuroinflammation, immune deregulation, impairment of neuronal-glial communication, and neurotoxic agents appear to be the major factors triggering neuronal degeneration, and the balance among these seems to vary from patient to patient. Although diverse, these factors induce deleterious signaling through different sets of neuronal receptors that converge in the hyperphosphorylation of tau molecules. Thus, tau hyperphosphorylation constitutes a common final pathway for most of the altered molecular and cellular factors that eventually result in degenerating neurons. This raises the question as to precisely what triggers the pathological phosphorylation. We have shown that Aβ oligomers, oxygen free radicals, and iron overload destabilize the equilibrium between the activities of protein phosphatases and kinases involved in tau assembly. Furthermore, overproduction or processing alterations of trophic factors such as NGF by activated glial cells trigger signaling cascades via p75, leading to cdk5 activation, followed by tau hyperphosphorylation and neuronal death. The cytokines TNFα, IL-1, and IL-6 induce activation of the cdk5/p35 complex, which causes tau phosphorylation.

Converging lines of evidence reveal the involvement of innate immunity (in contrast with the more widely acknowledged, but probably less-important involvement of adaptive immunity) and the role of inflammatory processes in the development of AD-associated neuronal changes. While methodological challenges cannot be ruled out in the interpretation of the so far confusing and sometimes even contradictory clinical trials, inflammation is essential in virtually all animal models for AD-like lesions. Taken together, these observations indicate that slowly accumulating danger/alarm signals to the innate immune system interfere with the balance of protective versus degeneration-promoting mechanisms, shifting the equilibrium toward neurodegeneration that involves deregulation of protein kinases cdk5 and GSKβ, tau hyperphosphorylation, and its aggregation into anomalous polymers in the neuronal cytoskeleton that constitutes the converging result of a large array of risk factors over time. These mediate the inexorable worsening of cognitive manifestations along with neuronal degeneration and the eventual appearance of tardy lesions such as SP and NFTs. This new theoretical framework based on recent experimental findings may serve as a powerful tool in the development of the much-sought biomarkers and in vivo imaging technology for the early diagnosis of AD. This will also help in the design of effective interventions to both treat and perhaps even prevent this increasingly prevalent brain disorder.