Wolframin-1–expressing neurons in the entorhinal cortex propagate tau to CA1 neurons and impair hippocampal memory in mice
Open Access
- 15 September 2021
- journal article
- research article
- Published by American Association for the Advancement of Science (AAAS) in Science Translational Medicine
- Vol. 13 (611), eabe8455
- https://doi.org/10.1126/scitranslmed.abe8455
Abstract
Abnormally phosphorylated tau, an early neuropathologic marker of Alzheimer’s disease (AD), first occurs in the brain’s entorhinal cortex layer II (ECII) and then spreads to the CA1 field of the hippocampus. Animal models of tau propagation aiming to recapitulate this phenomenon mostly show tau transfer from ECII stellate neurons to the dentate gyrus, but tau pathology in the dentate gyrus does not appear until advanced stages of AD. Wolframin-1–expressing (Wfs1+) pyramidal neurons have been shown functionally to modulate hippocampal CA1 neurons in mice. Here, we report that Wfs1+ pyramidal neurons are conserved in the ECII of postmortem human brain tissue and that Wfs1 colocalized with abnormally phosphorylated tau in brains from individuals with early AD. Wfs1+ neuron–specific expression of human P301L mutant tau in mouse ECII resulted in transfer of tau to hippocampal CA1 pyramidal neurons, suggesting spread of tau pathology as observed in the early Braak stages of AD. In mice expressing human mutant tau specifically in the ECII brain region, electrophysiological recordings of CA1 pyramidal neurons showed reduced excitability. Multielectrode array recordings of optogenetically stimulated Wfs1+ ECII axons resulted in reduced CA1 neuronal firing. Chemogenetic activation of CA1 pyramidal neurons showed a reduction in c-fos+ cells in the CA1. Last, a fear conditioning task revealed deficits in trace and contextual memory in mice overexpressing human mutant tau in the ECII. This work demonstrates tau transfer from the ECII to CA1 in mouse brain and provides an early Braak stage preclinical model of AD.Keywords
This publication has 50 references indexed in Scilit:
- Allen Brain Atlas: an integrated spatio-temporal portal for exploring the central nervous systemNucleic Acids Research, 2012
- Human P301L-Mutant Tau Expression in Mouse Entorhinal-Hippocampal Network Causes Tau Aggregation and Presynaptic Pathology but No Cognitive DeficitsPLOS ONE, 2012
- Fiji: an open-source platform for biological-image analysisNature Methods, 2012
- Propagation of Tau Pathology in a Model of Early Alzheimer's DiseaseNeuron, 2012
- Trans-Synaptic Spread of Tau Pathology In VivoPLOS ONE, 2012
- CA1 neurons in the human hippocampus are critical for autobiographical memory, mental time travel, and autonoetic consciousnessProceedings of the National Academy of Sciences of the United States of America, 2011
- Anterior Cingulate Synapses in Prefrontal Areas 10 and 46 Suggest Differential Influence in Cognitive ControlJournal of Neuroscience, 2010
- Synapses with Inhibitory Neurons Differentiate Anterior Cingulate from Dorsolateral Prefrontal Pathways Associated with Cognitive ControlNeuron, 2009
- Tau Suppression in a Neurodegenerative Mouse Model Improves Memory FunctionScience, 2005
- Neuropathological stageing of Alzheimer-related changesActa Neuropathologica, 1991