Abstract
Our recent work on genetic epilepsy (GE) has identified common mechanisms between GE and neurodegenerative diseases including Alzheimer’s disease (AD). Although both disorders are seemingly unrelated and occur at opposite ends of the age spectrum, it is likely there are shared mechanisms and studies on GE could provide unique insights into AD pathogenesis. Neurodegenerative diseases are typically late-onset disorders, but the underlying pathology may have already occurred long before the clinical symptoms emerge. Pathophysiology in the early phase of these diseases is understudied but critical for developing mechanism-based treatment. In AD, increased seizure susceptibility and silent epileptiform activity due to disrupted excitatory/inhibitory (E/I) balance has been identified much earlier than cognition deficit. Increased epileptiform activity is likely a main pathology in the early phase that directly contributes to impaired cognition. It is an enormous challenge to model the early phase of pathology with conventional AD mouse models due to the chronic disease course, let alone the complex interplay between subclinical nonconvulsive epileptiform activity, AD pathology, and cognition deficit. We have extensively studied GE, especially with gene mutations that affect the GABA pathway such as mutations in GABAA receptors and GABA transporter 1. We believe that some mouse models developed for studying GE and insights gained from GE could provide unique opportunity to understand AD. These include the pathology in early phase of AD, endoplasmic reticulum (ER) stress, and E/I imbalance as well as the contribution to cognitive deficit. In this review, we will focus on the overlapping mechanisms between GE and AD, the insights from mutations affecting GABAA receptors, and GABA transporter 1. We will detail mechanisms of E/I imbalance and the toxic epileptiform generation in AD, and the complex interplay between ER stress, impaired membrane protein trafficking, and synaptic physiology in both GE and AD.
Highlights
Introduction iationsAlzheimer’s disease (AD) is a common form of dementia and a massive public health burden, but there is currently no effective treatment that can modify the disease process or delay the disease onset
We demonstrated that the mutations in GABRG2 associated with severe epilepsy have mutant protein accumulation and aggregation, while the mutations in the same gene associated with mild epilepsy do not have the mutant protein accumulation and aggregation [30,60]
We have extensively studied the mouse models of genetic epilepsy (GE) with mutations in GABAA receptor subunit genes, and we found that the GABRG2(Q390X) mutation, which led to the aggregation of gamma-aminobutyric acid (GABA) receptor γ2 subunit and increased endoplasmic reticulum (ER) stress, was associated with a more severe seizure phenotype [77]
Summary
AD as a disease entity has been known for over 100 years. The pathological hallmarks of AD are extracellular amyloid plaques and intraneuronal neurofibrillary tangles, whose building blocks are amyloid-β (Aβ) peptides and phosphorylated tau, respectively. It is generally accepted that the histopathological findings in AD can be categorized into four central mechanisms: amyloid plaques (Aβ accumulation), neurofibrillary tangles tau hyperphosphorylation, neuroinflammation, and vascular dysfunction. The macroscopic changes of AD brains are characterized by parenchymal atrophy and enlarged ventricles, due to progressive neuronal loss beginning in and spreading from the entorhinal cortex in the medial temporal lobe [12,13]. These gross changes in relevant brain regions for memory and executive function correlate with impaired cognition in AD [14]
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