TY - JOUR
T1 - Loss of LAMP5 interneurons drives neuronal network dysfunction in Alzheimer's disease
AU - Deng, Yuanyuan
AU - Bi, Mian
AU - Delerue, Fabien
AU - Forrest, Shelley L.
AU - Chan, Gabriella
AU - van der Hoven, Julia
AU - van Hummel, Annika
AU - Feiten, Astrid F.
AU - Lee, Seojin
AU - Martinez-Valbuena, Ivan
AU - Karl, Tim
AU - Kovacs, Gabor G.
AU - Morahan, Grant
AU - Ke, Yazi D.
AU - Ittner, Lars M.
PY - 2022
Y1 - 2022
N2 - 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.
AB - 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.
UR - https://hdl.handle.net/1959.7/uws:77413
U2 - 10.1007/s00401-022-02457-w
DO - 10.1007/s00401-022-02457-w
M3 - Article
SN - 0001-6322
VL - 144
SP - 637
EP - 650
JO - Acta Neuropathologica
JF - Acta Neuropathologica
ER -