Linking Aβ and Tau in Late-Onset Alzheimer's Disease: A Dual Pathway Hypothesis

Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Department of Neurology, Columbia University College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
Neuron (Impact Factor: 15.05). 12/2008; 60(4):534-42. DOI: 10.1016/j.neuron.2008.11.007
Source: PubMed


Alzheimer's disease is characterized by abnormal elevation of Abeta peptide and abnormal hyperphosphorylation of the tau protein. The "amyloid hypothesis," which is based on molecular defects observed in autosomal-dominant early-onset Alzheimer's disease (EOAD), suggests a serial model of causality, whereby elevation of Abeta drives other disease features including tau hyperphosphorylation. Here, we review recent evidence from drug trials, genetic studies, and experimental work in animal models that suggests that an alternative model might exist in late-onset AD (LOAD), the complex and more common form of the disease. Specifically, we hypothesize a "dual pathway" model of causality, whereby Abeta and tau can be linked by separate mechanisms driven by a common upstream driver. This model may account for the results of recent drug trials and, if confirmed, may guide future drug development.

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    • "Il pourrait exister un lien entre ces deux cascades, car les dépôts d'oligomères en plaques diffuses seraient responsables d'une activation microgliale et astrocytaire, puis d'une réponse inflammatoire et d'un stress oxydatif qui altéreraient ensuite les activités kinase et phosphatase enzymatiques. Cette altération de l'activité kinase et phosphatase serait impliquée dans l'hyperphosphorylation de la protéine Tau, et donc secondairement dans le développement de la DNF[5]. Un modèle dynamique a été proposé par Hardy et Allsop[6]dans lequel l'effet toxique des peptides amyloïdes favorise une cascade physiopathologique comprenant la phosphorylation des protéines tau, la mort cellulaire et in fine l'atrophie cérébrale. "
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    • "" Primary age-related tauopathy " (PART) has recently been proposed to describe a pathology that is commonly observed in the brains of older individuals (Crary et al., 2014). From this perspective , Aβ and tau can increase the risk of AD via independent mechanisms that work together to induce synaptic and neuronal loss (Small and Duff, 2008). This idea does not exclude the possibility that Aβ can induce tau pathology, rather it suggests that tau pathology can occur independently of Aβ and that individuals who have PART might be more vulnerable to Aβ if the latter starts to accumulate. "

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    • "Many studies have shown that, even at the mild cognitive impairment stage of AD, extensive amyloid and tau pathologies are already present (Nelson et al., 2012). Also, it has been proposed that, in sporadic LOAD, tau pathology is not simply downstream of Ab-related pathology, but that these pathologies could be generated by dual pathways that can interact synergistically (Small and Duff, 2008; Yoshiyama et al., 2013). If this holds true, it would be essential to devise an approach that could simultaneously and effectively target both pathologies. "
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