Propagation of tau pathology in a model of early Alzheimer’s disease

By Alix de Calignon, M. Polydoro, Marc Suárez-Calvet, Christopher M. William, David H. Adamowicz, Katherine J. Kopeikina, Rose Pitstick, N. Sahara, K. Ashe, G. Carlson and 2 more. Neuron, 2012

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Summary Neurofibrillary tangles advance from layer II of the entorhinal cortex (EC-II) toward limbic and association cortices as Alzheimer disease (AD) evolves. However, the mechanism involved in this hierarchical pattern of disease progression is unknown. We describe a transgenic mouse model in which overexpression of human tau P301L is restricted to EC-II. Tau pathology progresses from EC transgene-expressing neurons to neurons without detectable transgene expression, first to EC neighboring cells, followed by propagation to neurons downstream in the synaptic circuit such as the dentate gyrus, CA fields of the hippocampus, and cingulate cortex. Human tau protein spreads to these regions and co-aggregates with endogenous mouse tau. With age, synaptic degeneration occurs in the entorhinal target zone and EC neurons are lost. These data suggest that a sequence of progressive misfolding of tau proteins, circuit-based transfer to new cell populations, and deafferentation induced degeneration are part of a process of tau-induced neurodegeneration.

Subfields: Cellular and Molecular Neuroscience, Physiology, Psychiatry and Mental health

View Paper: https://www.semanticscholar.org/paper/3073c2866131b1476d88f4640ca98cc11974a862

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Citations in the corpus

Primary age-related tauopathy (PART): a common pathology associated with human aging (2014, background): “synaptically [34, 35, 38, 46, 47, 57, 91], it is notable that PART-type pathology generally does not progress to the isocortical Braak stages (i.”
Synaptic energy use and supply. (2012, background): “Furthermore, abnormal tau can spread transsynaptically, propagating AD pathology and thus disrupting synaptic function throughout anatomically connected neurons (Liu et al., 2012b; de Calignon et al., 2012).”
Tau Protein Hyperphosphorylation and Aggregation in Alzheimer’s Disease and Other Tauopathies, and Possible Neuroprotective Strategies (2016, background): “The most recent data obtained indicate that tau pathology indeed may be induced and propagated after the injection of tau oligomers or aggregates in either wild-type or mutated MAPT transgenic mice [164], and that tau aggregates can be transferred from cell to cell in vitro [164,165] and in vivo [16”
Heparan sulfate proteoglycans mediate internalization and propagation of specific proteopathic seeds (2013, background): “(2007) beta-Sheet structured beta-amyloid(1-40) perturbs phosphatidylcholine model membranes.”
Mitochondrial Dysfunction in Neurodegenerative Diseases (2012, background): “…to neurodegenerative diseases with genetic experiments providing convincing evidence that mutant A␤, ␣-synuclein, and tau can be transferred between neighboring neurons, and then induce pathological changes in these neurons (Harris et al., 2010; Luk et al., 2012; de Calignon et al., 2012).”