Loss of LAMP5 interneurons drives neuronal network dysfunction in Alzheimer's disease

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

doi:10.1007/s00401-022-02457-w

Loss of LAMP5 interneurons drives neuronal network dysfunction in Alzheimer's disease

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^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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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.

Original language	English
Pages (from-to)	637-650
Number of pages	14
Journal	Acta Neuropathologica
Volume	144
Issue number	4
Early online date	3 Jul 2022
DOIs	https://doi.org/10.1007/s00401-022-02457-w
Publication status	Published - Oct 2022

Bibliographical note

Copyright the Author(s) 2022. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

Keywords

Alzheimer's disease
Amyloid-β
Tau
Hyperexcitation
Neuronal network
LAMP5

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10.1007/s00401-022-02457-wLicence: CC BY

Publisher version (open access)Final published version, 7.9 MBLicence: CC BY

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Deng, Y., Bi, M., Delerue, F., Forrest, S. L., Chan, G., van der Hoven, J., van Hummel, A., Feiten, A. F., Lee, S., Martinez-Valbuena, I., Karl, T., Kovacs, G. G., Morahan, G., Ke, Y. D., & Ittner, L. M. (2022). Loss of LAMP5 interneurons drives neuronal network dysfunction in Alzheimer's disease. Acta Neuropathologica, 144(4), 637-650. https://doi.org/10.1007/s00401-022-02457-w

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abstract = "In Alzheimer{\textquoteright}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.",

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

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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.

N1 - Copyright the Author(s) 2022. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

PY - 2022/10

Y1 - 2022/10

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.

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Loss of LAMP5 interneurons drives neuronal network dysfunction in Alzheimer's disease

Abstract

Bibliographical note

Keywords

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Developing insight into the molecular origins of familial and sporadic frontotemporal dementia and amyotrophic lateral sclerosis

Single-session Introduction of Mutations in Parallel Lines (SIMPL)

Cite this

Loss of LAMP5 interneurons drives neuronal network dysfunction in Alzheimer's disease

Abstract

Bibliographical note

Keywords

Access to Document

Other files and links

Fingerprint

Projects

Developing insight into the molecular origins of familial and sporadic frontotemporal dementia and amyotrophic lateral sclerosis

Single-session Introduction of Mutations in Parallel Lines (SIMPL)

Cite this