Decreased extrasynaptic δ‐GABAA receptors in PNN‐associated parvalbumin interneurons correlates with anxiety in APP and tau mouse models of Alzheimer's disease

Jun 17, 2024British journal of pharmacology

Lower levels of special inhibitory receptors in protective interneurons linked to anxiety in Alzheimer's mouse models

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Abstract

Alzheimer's disease mouse models exhibited elevated anxiety correlated with cognitive decline and neuroinflammatory markers.

Anxiety and cognitive decline were observed in AppKI and App/MAPT mouse models of Alzheimer's disease.
Neuroinflammatory markers, including TREM2 and reactive astrocytes, were elevated in the AD models compared to wild-type controls.
There was an age-dependent reduction in δ-GABAR expression in specific neurons in AD mouse models.
Positive modulation of δ-GABARs using a selective compound decreased anxiety levels in the AD models.
Reduced anxiety was associated with decreased neuroinflammation and normalization of δ-GABAR expression.

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BACKGROUND: Alzheimer's disease (AD) is associated with gradual memory loss and anxiety which affects ~75% of AD patients. This study investigated whether AD-associated anxiety correlated with modulation of extrasynaptic δ-subunit-containing GABAreceptors (δ-GABARs) in experimental mouse models of AD. A A

EXPERIMENTAL APPROACH: We combined behavioural experimental paradigms to measure cognition performance, and anxiety with neuroanatomy and molecular biology, using familial knock-in (KI) mouse models of AD that harbour β-amyloid (Aβ) precursor protein App (App) with or without humanized microtubule-associated protein tau (MAPT), age-matched to wild-type control mice at three different age windows. NL-F

RESULTS: AppKI and App/MAPT AD models showed a similar magnitude of cognitive decline and elevated magnitude of anxiety correlated with neuroinflammatory hallmarks, including triggering receptor expressed on myeloid cells 2 (TREM2), reactive astrocytes and activated microglia consistent with accumulation of Aβ, tau and down-regulation of Wnt/β-catenin signalling compared to aged-matched WT controls. In both the CA1 region of the hippocampus and dentate gyrus, there was an age-dependent decline in the expression of δ-GABARs selectively expressed in parvalbumin (PV)-expressing interneurons, encapsulated by perineuronal nets (PNNs) in the AD mouse models compared to WT mice. In vivo positive allosteric modulation of the δ-GABARs, using a δ-selective-compound DS2, decreased the level of anxiety in the AD mouse models, which was correlated with reduced hallmarks of neuroinflammation, and 'normalisation' of the expression of δ-GABARs. NL-F NL-F A A A

CONCLUSIONS: Our data show that the δ-GABARs could potentially be targeted for alleviating symptoms of anxiety, which would greatly improve the quality of life of AD individuals. A

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Decreased extrasynaptic δ‐GABAA receptors in PNN‐associated parvalbumin interneurons correlates with anxiety in APP and tau mouse models of Alzheimer's disease

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