Aberrant excitatory neuronal activity and compensatory remodeling of inhibitory hippocampal circuits in mouse models of alzheimer’s disease.
Open accessAbstract
Neural network dysfunction may play an important role in Alzheimer's disease (AD). Neuronal circuits vulnerable to AD are also affected in human amyloid precursor protein (hAPP) transgenic mice. hAPP mice with high levels of amyloid-beta peptides in the brain develop AD-like abnormalities, including cognitive deficits and depletions of calcium-related proteins in the dentate gyrus, a region critically involved in learning and memory. Here, we report that hAPP mice have spontaneous nonconvulsive seizure activity in cortical and hippocampal networks, which is associated with GABAergic sprouting, enhanced synaptic inhibition, and synaptic plasticity deficits in the dentate gyrus. Many Abeta-induced neuronal alterations could be simulated in nontransgenic mice by excitotoxin challenge and prevented in hAPP mice by blocking overexcitation. Aberrant increases in network excitability and compensatory inhibitory mechanisms in the hippocampus may contribute to Abeta-induced neurological deficits in hAPP mice and, possibly, also in humans with AD.
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A relationship between Aβ production and epileptiform activity was established in the APP/PS1 transgenic mouse model as early as 4 months of age, prior to Aβ plaque deposits forming in the brain parenchyma.
“a relationship between Aβ production and epileptiform activity was established in the APP/PS1 transgenic mouse model as early as 4 months of age, prior to Aβ plaque deposits forming in the brain parenchyma [9, 10].”
From Microglia specific deletion of miR-155 in Alzheimer’s disease mouse models reduces amyloid-β pathology but causes hyperexcitability and seizures (2023) · cites this paper as [10]
Both cell autonomous and non-cell autonomous mechanisms contribute to epilepsy in AD.
“Recent reports suggest both cell autonomous and non-cell autonomous mechanisms are contributors to epilepsy in AD [7, 10].”
From Microglia specific deletion of miR-155 in Alzheimer’s disease mouse models reduces amyloid-β pathology but causes hyperexcitability and seizures (2023) · cites this paper as [10]
Alzheimer's disease may lead to hippocampal and cortical hyperexcitability as well as increased seizure susceptibility in both AD humans and rodent models.
“This may lead to hippocampal and cortical hyperexcitability as well as increased seizure susceptibility in both AD humans and rodent models (Palop et al., 2007; Roberson et al., 2011).”
From The Perineuronal ‘Safety’ Net? Perineuronal Net Abnormalities in Neurological Disorders (2018) · cites this paper as Palop et al., 2007
Perineuronal net loss in AD may contribute to altered E/I balance.
“Perineuronal net loss in AD may contribute to altered E/I balance (Palop et al., 2007; Sun et al., 2009)”
From The Perineuronal ‘Safety’ Net? Perineuronal Net Abnormalities in Neurological Disorders (2018) · cites this paper as Palop et al., 2007
Synaptogenic mechanisms of AD cognitive decline-network activation and deactivation deficits, abnormal oscillatory rhythmic activity, and network hypersynchrony-account for AD-related synaptic failure.
“From a functional standpoint, synaptogenic mechanisms of AD cognitive decline–that is, network activation and deactivation deficits, abnormal oscillatory rhythmic activity, and network hypersynchrony–account for AD-related synaptic failure (120–122).”
From The β-Secretase BACE1 in Alzheimer’s Disease (2021) · cites this paper as [122]
10-22% of Alzheimer's disease patients exhibit seizures, as do hAPPFAD mice, and the onset of these seizures precedes cognitive decline.
“10–22% of AD patients exhibit seizures [98–100], as do hAPPFAD mice [101], and the onset of these seizures precedes cognitive decline [102].”
From Apolipoprotein E4, inhibitory network dysfunction, and Alzheimer’s disease (2019) · cites this paper as [101]
β-amyloid (Aβ) could enhance translation of GABAA receptor (at α6 subunit) by phosphorylation of mTOR and ERK in cerebellum of experimental mice, and hence an increase in inhibitory transmission at synapse affects learning and memory process.
“It is evident that β-amyloid (Aβ) could also enhance the translation of GABAA receptor (at α6 subunit) by the phosphorylation of mTOR and ERK in the cerebellum of experimental mice [28,159,160], and hence an increase in inhibitory transmission at synapse affects the learning and memory process [161].”
From Acetylcholinesterase Inhibitory Potential of Various Sesquiterpene Analogues for Alzheimer’s Disease Therapy (2021) · cites this paper as [161]
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References 90 · Cited by 1,653
- Authors
- Palop, J. J., Chin, J., Roberson, E. D., Wang, J., Thwin, M. T., Bien-Ly, N., Yoo, J., Ho, K. O., Yu, G.-Q., Kreitzer, A., Finkbeiner, S., Noebels, J. L., & Mucke, L.
- Affiliations
- Gladstone Institutes (US)
- Baylor College of Medicine (US)
- Corresponding author
- Palop, Jorge J.
- Mucke, Lennart
- ORCID
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2007-09
- Volume
- 55
- Issue
- 5
- Pages
- 697-711
- ISSN
- 0896-6273 (ISSN-L)
- PMC
- PMC8055171
- OpenAlex
- W2004852048
- Cited by
- 1,653
- References
- 90
- Citations by year
- 2026: 76 · 2025: 109 · 2024: 115 · 2023: 114 · 2022: 115 · 2021: 133 · 2020: 101 · 2019: 100 · 2018: 101 · 2017: 87 · 2016: 86 · 2015: 74 · 2014: 76 · 2013: 58 · 2012: 83
- FWCI
- 31.98
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Foundation for the National Institutes of Health
- National Institutes of Health (1c06rr018928-01)
- National Institute on Aging (AG011385, R37AG011385, AG022074, P01AG022074, AG023501, R01AG011385, P50AG023501)
- National Institute of Neurological Disorders and Stroke (NS39074, K08NS054811, R01NS041787, R01NS039074, NS041787, NS54811, NS29709, R01NS029709)
- National Center for Research Resources (C06-RR-018928, RR018928)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD 024064, P30HD024064)
- 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 › Cognitive Neuroscience › Memory and Neural Mechanisms
- Keywords
- Alzheimer's disease, amyloid-beta, hippocampus, dentate gyrus, network excitability, nonconvulsive seizures, synaptic inhibition, synaptic plasticity, excitotoxicity, calcium-binding proteins, cognitive impairment
- MeSH terms
- Alzheimer Disease, Animals, Cognition Disorders, Disease Models, Animal, Epilepsy, gamma-Aminobutyric Acid, Humans, Mice, Transgenic, Neural Inhibition, Neural Pathways, Synaptic Transmission, Neuronal Plasticity, Neurotoxins, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Mice, Knockout, Dentate Gyrus, Neocortex, Mice
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