Inhibitory Interneuron Deficit Links Altered Network Activity and Cognitive Dysfunction in Alzheimer Model

Verret, Laure; Mann, Edward O.; Hang, Giao B.; Barth, Albert M.; Cobos, Inma; Ho, Kaitlyn; Devidze, Nino; Masliah, Eliezer; Kreitzer, Anatol C.; Módy, István; Mucke, Lennart; Palop, Jorge J.

doi:10.1016/j.cell.2012.02.046

Cited by 955 publications

(1,272 citation statements)

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“…We therefore crossed hTau‐A152T (L1) mice and hTau‐WT (L32) mice with hAPP transgenic mice from line J20 (hAPP‐J20) (Fig 11A–D). hAPP‐J20 mice have pathologically elevated levels of human Aβ in the brain, increased risk of early death (most likely from epileptic activity), and AD‐like features, including memory problems, behavioral alterations, synaptic impairments, amyloid plaques, neuritic dystrophy, astrocytosis, and microgliosis 49, 50, 51, 52, 53.…”

Section: Resultsmentioning

confidence: 99%

Expression of A152T human tau causes age‐dependent neuronal dysfunction and loss in transgenic mice

et al. 2016

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A152T‐variant human tau (hTau‐A152T) increases risk for tauopathies, including Alzheimer's disease. Comparing mice with regulatable expression of hTau‐A152T or wild‐type hTau (hTau‐WT), we find age‐dependent neuronal loss, cognitive impairments, and spontaneous nonconvulsive epileptiform activity primarily in hTau‐A152T mice. However, overexpression of either hTau species enhances neuronal responses to electrical stimulation of synaptic inputs and to an epileptogenic chemical. hTau‐A152T mice have higher hTau protein/mRNA ratios in brain, suggesting that A152T increases production or decreases clearance of hTau protein. Despite their functional abnormalities, aging hTau‐A152T mice show no evidence for accumulation of insoluble tau aggregates, suggesting that their dysfunctions are caused by soluble tau. In human amyloid precursor protein (hAPP) transgenic mice, co‐expression of hTau‐A152T enhances risk of early death and epileptic activity, suggesting copathogenic interactions between hTau‐A152T and amyloid‐β peptides or other hAPP metabolites. Thus, the A152T substitution may augment risk for neurodegenerative diseases by increasing hTau protein levels, promoting network hyperexcitability, and synergizing with the adverse effects of other pathogenic factors.

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Section: Resultsmentioning

confidence: 99%

Expression of A152T human tau causes age‐dependent neuronal dysfunction and loss in transgenic mice

et al. 2016

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“…These mice exhibit robust epileptic activity and have dysregulated gamma activity 22, 26. A side‐by‐side comparison of EEG recordings in SYN and hAPP mice matched for age and background strain revealed clear differences in resting spectral power.…”

Section: Resultsmentioning

confidence: 99%

“…Recordings from other brain regions and task‐related spectral analyses may provide additional insights into neuronal network dysfunction. For example, EEG recordings over the frontal cortex might be more suitable for assessing potential contributions of cholinergic deficits to spectral alterations in SYN mice, and analysis of individual EEG recordings in actively exploring mice could help reveal the kind of dysregulation of gamma oscillations we observed in hAPP mice 22. Additionally, our EEG recordings were limited to one transgenic line.…”

Section: Discussionmentioning

confidence: 99%

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Network dysfunction in α‐synuclein transgenic mice and human Lewy body dementia

Morris

Sanchez

Verret

et al. 2015

Ann Clin Transl Neurol

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ObjectiveDementia with Lewy bodies (DLB) is associated with the accumulation of wild‐type human α‐synuclein (SYN) in neurons and with prominent slowing of brain oscillations on electroencephalography (EEG). However, it remains uncertain whether the EEG abnormalities are actually caused by SYN.MethodsTo determine whether SYN can cause neural network abnormalities, we performed EEG recordings and analyzed the expression of neuronal activity‐dependent gene products in SYN transgenic mice. We also carried out comparative analyses in humans with DLB.ResultsWe demonstrate that neuronal expression of SYN in transgenic mice causes a left shift in spectral power that closely resembles the EEG slowing observed in DLB patients. Surprisingly, SYN mice also had seizures and showed molecular hippocampal alterations indicative of aberrant network excitability, including calbindin depletion in the dentate gyrus. In postmortem brain tissues from DLB patients, we found reduced levels of calbindin mRNA in the dentate gyrus. Furthermore, nearly one quarter of DLB patients showed myoclonus, a clinical sign of aberrant network excitability that was associated with an earlier age of onset of cognitive impairments. In SYN mice, partial suppression of epileptiform activity did not alter their shift in spectral power. Furthermore, epileptiform activity in human amyloid precursor protein transgenic mice was not associated with a left shift in spectral power.InterpretationWe conclude that neuronal accumulation of SYN slows brain oscillations and, in parallel, causes aberrant network excitability that can escalate into seizure activity. The potential role of aberrant network excitability in DLB merits further investigation.

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“…Transgene insertion may destroy endogenous gene loci (Kuro‐o et al , 1997; Verret et al , 2012; Saito et al , 2016). …”

Section: Limitations Of First‐generation Mouse Modelsmentioning

confidence: 99%

APP mouse models for Alzheimer's disease preclinical studies

et al. 2017

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Animal models of human diseases that accurately recapitulate clinical pathology are indispensable for understanding molecular mechanisms and advancing preclinical studies. The Alzheimer's disease (AD) research community has historically used first‐generation transgenic (Tg) mouse models that overexpress proteins linked to familial AD (FAD), mutant amyloid precursor protein (APP), or APP and presenilin (PS). These mice exhibit AD pathology, but the overexpression paradigm may cause additional phenotypes unrelated to AD. Second‐generation mouse models contain humanized sequences and clinical mutations in the endogenous mouse App gene. These mice show Aβ accumulation without phenotypes related to overexpression but are not yet a clinical recapitulation of human AD. In this review, we evaluate different APP mouse models of AD, and review recent studies using the second‐generation mice. We advise AD researchers to consider the comparative strengths and limitations of each model against the scientific and therapeutic goal of a prospective preclinical study.

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Inhibitory Interneuron Deficit Links Altered Network Activity and Cognitive Dysfunction in Alzheimer Model

Cited by 955 publications

References 59 publications

Expression of A152T human tau causes age‐dependent neuronal dysfunction and loss in transgenic mice

Expression of A152T human tau causes age‐dependent neuronal dysfunction and loss in transgenic mice

Network dysfunction in α‐synuclein transgenic mice and human Lewy body dementia

APP mouse models for Alzheimer's disease preclinical studies

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