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Cited by 50Alzheimer's disease research and treatmentsNeuroscience and Neuropharmacology ResearchNeuroinflammation and Neurodegeneration Mechanisms

Reduced excitatory neuron activity and interneuron-type-specific deficits in a mouse model of Alzheimer’s disease

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Algamal, Moustafa, Russ, Alyssa N., Miller, Morgan R., Hou, Steven S., Maci, Megi, Munting, Leon P., Zhao, Qiuchen, Gerashchenko, Dmitry +2 more·2022·Communications Biology
DOI 10.1038/s42003-022-04268-xPMC PMC9718858

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Abstract

Alzheimer’s disease (AD) is characterized by progressive memory loss and cognitive decline. These impairments correlate with early alterations in neuronal network activity in AD patients. Disruptions in the activity of individual neurons have been reported in mouse models of amyloidosis. However, the impact of amyloid pathology on the spontaneous activity of distinct neuronal types remains unexplored in vivo. Here we use in vivo calcium imaging with multiphoton microscopy to monitor and compare the activity of excitatory and two types of inhibitory interneurons in the cortices of APP/PS1 and control mice under isoflurane anesthesia. We also determine the relationship between amyloid accumulation and the deficits in spontaneous activity in APP/PS1 mice. We show that somatostatin-expressing (SOM) interneurons are hyperactive, while parvalbumin-expressing interneurons are hypoactive in APP/PS1 mice. Only SOM interneuron hyperactivity correlated with proximity to amyloid plaque. These inhibitory deficits were accompanied by decreased excitatory neuron activity in APP/PS1 mice. Our study identifies cell-specific neuronal firing deficits in APP/PS1 mice driven by amyloid pathology. These findings highlight the importance of addressing the complexity of neuron-specific deficits to ameliorate circuit dysfunction in Alzheimer’s disease.

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  • Evidence that FTD tau pathology leads to similar network dysfunction suggests converging network dysfunction in AD and primary tauopathies.

    “Evidence that FTD tau pathology leads to similar network dysfunction suggests converging network dysfunction in AD and primary tauopathies51–53.”

    From The R136S mutation in the APOE3 gene confers resilience against tau pathology via inhibition of the cGAS-STING-IFN pathway (2025) · cites this paper as [52]

    The Discussion reports network dysfunction in an APP/PS1 mouse model of Alzheimer’s disease, including altered interneuron and excitatory-neuron activity. Our copy does not report evidence that FTD tau pathology causes similar dysfunction or establish convergence between AD and primary tauopathies; searches for FTD and tau-related circuit dysfunction did not find that comparison. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • FTD tau pathology leads to network dysfunction similar to that in AD, suggesting converging network dysfunction in AD and primary tauopathies.

    “The revelation that frontotemporal dementia (FTD) tau pathology led to similar network dysfunction suggests converging network dysfunction in AD and primary tauopathies49–51”

    From <i>APOE3</i> - <i>R136S</i> mutation confers resilience against tau pathology via cGAS-STING-IFN inhibition (2024) · cites this paper as [50]

    The Discussion reports network dysfunction in AD and cell-type-specific activity deficits in APP/PS1 mice. It does not address FTD tau pathology or compare its network effects with AD, so it does not support the claimed convergence. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

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Authors
Algamal, M., Russ, A. N., Miller, M. R., Hou, S. S., Maci, M., Munting, L. P., Zhao, Q., Gerashchenko, D., Bacskai, B. J., & Kastanenka, K. V.
Affiliations
Harvard University (US)
Corresponding author
  • Bacskai, Brian J.
  • Kastanenka, Ksenia V.
ORCID
Venue
Communications Biology
Publisher
Springer Science and Business Media LLC
Published
2022-12-02
Volume
5
Issue
1
Pages
1323-1323
ISSN
2399-3642 (ISSN-L)
DOI
10.1038/s42003-022-04268-x
PMC
PMC9718858
OpenAlex
W4310555362
Cited by
50
References
7
Citations by year
2026: 12 · 2025: 8 · 2024: 20 · 2023: 9 · 2022: 1
FWCI
5.88
Type
journal article
Language
en
Open access
Licence
Locations
  • Communications Biology (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • BrightFocus Foundation (A2021001F)
  • U.S. Department of Health & Human Services | NIH | National Institute on Aging (RF1AG061774)
  • Alzheimer’s Association (AARG-18-52336)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
Alzheimer's disease, APP/PS1 mice, amyloid plaques, spontaneous neuronal activity, excitatory neurons, somatostatin interneurons, parvalbumin interneurons, neuronal network dysfunction, cortical circuits, in vivo calcium imaging
MeSH terms
Alzheimer Disease, Amyloidosis, Animals, Disease Models, Animal, Interneurons, Neurons, Mice, Plaque, Amyloid, Amyloidogenic Proteins

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