Loss of LAMP5 Interneurons Drives Neuronal Network Dysfunction in Alzheimer’s Disease

Authors

Yuanyuan Deng
Mian Bi
Fabien Delerue
Shelley L Forrest
Gabriella Chan
Julia van der Hoven
Annika van Hummel
Astrid F Feiten
Seojin Lee
Ivan Martinez-Valbuena
Tim Karl
Gabor G Kovacs
Grant Morahan
Yazi D Ke
Lars M Ittner

Publication Date

10-1-2022

Journal

Acta Neuropathologica

Abstract

In Alzheimer's disease (AD), where amyloid-β (Aβ) and tau deposits in the brain, hyperexcitation of neuronal networks is an underlying disease mechanism, but its cause remains unclear. Here, we used the Collaborative Cross (CC) forward genetics mouse platform to identify modifier genes of neuronal hyperexcitation. We found LAMP5 as a novel regulator of hyperexcitation in mice, critical for the survival of distinct interneuron populations. Interestingly, synaptic LAMP5 was lost in AD brains and LAMP5 interneurons degenerated in different AD mouse models. Genetic reduction of LAMP5 augmented functional deficits and neuronal network hypersynchronicity in both Aβ- and tau-driven AD mouse models. To this end, our work defines the first specific function of LAMP5 interneurons in neuronal network hyperexcitation in AD and dementia with tau pathology.

Keywords

Alzheimer’s disease, Amyloid-β, Tau, Hyperexcitation, Neuronal network, LAMP5

DOI

10.1007/s00401-022-02457-w

PMID

35780436

PMCID

PMC9467963

PubMedCentral® Posted Date

July 2022

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes