Wolframin-1-Expressing Neurons in The Entorhinal Cortex Propagate Tau To CA1 Neurons and Impair Hippocampal Memory in Mice

9/20/21, 7:32 PM Wolframin-1–expressing neurons in the entorhinal cortex propagate tau to CA1 neurons and impair hippocampal memory
CA1 neurons and impair hippocampal memory in mice
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HOME  SCIENCE TRANSLATIONAL MEDICINE  VOL. 13, NO. 611  WOLFRAMIN-1–EXPRESSING NEURONS IN THE ENTORHINAL CORTEX PROPAGATE TAU TO CA1 NEURONS AND IMPAIR HIPPOCAMPAL…
RESEARCH ARTICLE ALZHEIMER’S DISEASE

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Wolframin-1–expressing neurons in the entorhinal cortex propagate

tau to CA1 neurons and impair hippocampal memory in mice
JEAN-CHRISTOPHE DELPECH
, DHRUBA PATHAK, MERINA VARGHESE , SRINIDHI VENKATESAN KALAVAI , EMMA C. HAYS , PATRICK R. HOF , W. EVAN JOHNSON , SEIKO IKEZU, MARIA MEDALLA ,
JENNIFER I. LUEBKE
, AND TSUNEYA IKEZU 
SCIENCE TRANSLATIONAL MEDICINE • 15 Sep 2021 • Vol 13, Issue 611 • DOI: 10.1126/scitranslmed.abe8455
    GET ACCESS
A neuronal highway for tau
Abnormally phosphorylated tau has been observed in the entorhinal cortex layer II (ECII) of the brain and from
there spreads to the hippocampal CA1 region during the early stages of Alzheimer’s disease. Here, Delpech et
al. develop an animal model that recapitulates this early tau spreading pathology. They show that expressing
human mutant tau specifically in Wolframin-1–positive neurons of the ECII of mouse brain resulted in transfer
of tau specifically to the hippocampal CA1 area. This was accompanied by memory impairment and reduced
activity of CA1 pyramidal neurons, suggesting that this neuronal pathway should be investigated further in
Alzheimer’s disease.
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 hippocam-
pal CA1 neurons in mice. Here, we report that Wfs1+ pyramidal neurons are conserved in the ECII of post-
mortem human brain tissue and that Wfs1 colocalized with abnormally phosphorylated tau in brains from in-
dividuals 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, elec-
trophysiological 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.
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9/20/21, 7:32 PM Wolframin-1–expressing neurons in the entorhinal cortex propagate tau to CA1 neurons and impair hippocampal memory in mice
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9/20/21, 7:32 PM Wolframin-1–expressing neurons in the entorhinal cortex propagate tau to CA1 neurons and impair hippocampal memory

CA1 neurons and impair hippocampal memory in mice

RESEARCH ARTICLE ALZHEIMER’S DISEASE

Wolframin-1–expressing neurons in the entorhinal cortex propagate

A neuronal highway for tau

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View/request a protocol for this paper from Bio-protocol.

REFERENCES AND NOTES

11 A. de Calignon, M. Polydoro, M. Suárez-Calvet, C. William, D. H. Adamowicz, K. J. Kopeikina, R. Pitstick, N. Sahara, K. H. Ashe, G. A.

14 B. L. Roth, DREADDs for neuroscientists. Neuron 89, 683–694 (2016).

Alzheimer’s disease. Neuroscience 112, 75–91 (2002).

No eLetters have been published for this article yet.

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Attenuation of peripheral serotonin inhibits tumor growth and enhances im-

Wolframin-1–expressing neurons in the entorhinal cortex propagate tau to

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