Seizures exacerbate excitatory‐inhibitory imbalance and tau seeding effects in 5XFAD mice
نویسندگان
چکیده
Background Alzheimer’s Disease (AD) neuropathology is largely driven by two pathological proteins, tau, and ß-amyloid, both of which induce neuronal hyperexcitability are thought to play a role in the high comorbidity between AD epilepsy. Central progression spread tau along networks likely via activity. Our previous work suggests bidirectional relationship epilepsy with seizures inducing pathology vice versa (Gourmaud et al. Brain, 2021; awab268). Additionally, there evidence excitatory-inhibitory (E:I) imbalance reminiscent E:I imbalances involved epileptogenesis. Thus, we hypothesized that can exacerbate models this enhanced promotes propagation tau. Method We utilized Five times familial (5XFAD) model an established pentylenetetrazol (PTZ) kindling method these WT littermates. To seen AD, cohort animals also underwent intracerebral injection human AD-derived (AD-tau) into hippocampus overlying cortex prior seizure induction. Western blots were performed for Cl− transporters, K+- Cl−cotransporter 2 (KCC2) Na+-K+-Cl− cotransporter 1 (NKCC1), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) subunits, GluA2 GluA1, GABAAR subunits α1 α3, given their roles balance. AD-tau injected mice examined western blot phospho-tau AT8 [Ser202; Thr205] AT180 [Thr231] sites proximal (hippocampus) distal (frontal cortex) site determine effects on propagation. Result PTZ-kindling dysregulation Cl- NKCC1 KCC2 (p<0.05, n = 12-19) GluA2/GluA1 ratios 5XFAD mice, while showed decreased GABAARα1 12-19). No significant changes nor AT180, but induction elevated levels frontal across genotypes 5-9). Conclusion data suggest mice. drugs targeting mechanisms balance or controlling antiseizure medication shows therapeutic efficacy patients comorbid seizures.
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ژورنال
عنوان ژورنال: Alzheimers & Dementia
سال: 2023
ISSN: ['1552-5260', '1552-5279']
DOI: https://doi.org/10.1002/alz.067907