Gaikwad S, Puangmalai N, Bittar A, Montalbano M, Garcia S, McAllen S, Bhatt N, Sonawane M, Sengupta U, Kayed R. Tau oligomer induced HMGB1 release contributes to cellular senescence and neuropathology linked to Alzheimer's disease and frontotemporal dementia. Cell Rep. 2021 Jul 20;36(3):109419. PubMed.

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  1. In the classical amyloid hypothesis, pathogenic Aβ species impair brain functions and structures through tau hyperphosphorylation and oligomerization. In this interesting paper, the authors instead propose a novel hypothesis that tau oligomers induce senescence of astrocytes by increasing the release of HMGB1. The hypothesis is highly novel and has a great translational significance as it unravels a new drug target.

    A huge amount of literature supports that soluble tau oligomers in neurons impair synaptic and cognitive functions. Treatment with HMGB1 inhibitors here probably affect both neurons and glia. Moreover, the aged human tau transgenic mice used here do not contain all regulatory elements of human tau genes and have no change in Aβ. Tau expression levels and the proportion of all six isoforms of tau proteins may not be the same as in human brains. Therefore, the model will probably not recapture all aspects of the cellular changes that occur in Alzheimer’s disease and other neurodegenerative diseases.

    It will be interesting for further studies to test how the proposed astrocyte pathway fits in the big picture of the pathophysiology of tauopathies.

    View all comments by Dezhi Liao

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