Age‑dependent concomitant changes in synaptic function and GABAergic pathway in the APP/PS1 mouse model

Abstract

Synaptic dysfunction is a well-documented manifestation in animal models of Alzheimer's disease pathology. In this context, numerous studies have documented reduction in the functionality of synapses in various models. In addition, recent research has shed more light on increased excitability and its link to seizures and seizure-like activities in AD patients as well as in mouse models. These reports of hyperexcitability contradict the observed reduction in synaptic function and have been suggested to be as a result of the interplay between inhibitory and excitatory neuronal mechanism. The present study therefore investigates functional deficiency in the inhibitory system as complementary to the identified alterations in the glutamate excitatory pathway in AD. Since synaptic function deficit in AD is typically linked to progression/pathology of the disease, it is important to determine whether the deficits in the GABAergic system are functional and can be directly linked to the pattern of the disruption documented in the glutamate system. To build on previous research in this field, experiments were designed to determine if previously documented synaptic dysfunction in AD models is concomitantly observed with excitation/inhibition imbalance as suggested by observation of seizure and seizure-like pathology in such models. We report changes in synaptic function in aged APPPS1 mice not observable in the younger cohort. These changes in synaptic function are furthermore accompanied by alteration in the GABAergic neurotransmission. Thus, age-dependent alteration in the inhibitory/ excitatory balance might underpin the symptomatic changes observed with the progression of Alzheimer's disease pathology including sleep disturbance and epileptic events.

Soticlestat, a novel cholesterol 24-hydroxylase inhibitor shows a therapeutic potential for neural hyperexcitation in mice

“…Originally developed as an AD mouse model, APP/PS1-Tg mice have also been recognized as a model of excitatory/inhibitory imbalance, including seizure-related sudden death 30 , 31 , 35 – 37 . The strain kept in our facility showed approximate 50% mortality over the first 3 months after birth.…”

Genetic deletion of CB1 cannabinoid receptors exacerbates the Alzheimer-like symptoms in a transgenic animal model

“…Aβ peptide is known to induce synaptic dysfunction during early stages of AD by deregulating molecular organization of the postsynaptic density (Liu et al, 2010;Oyelami et al, 2016). Because of this, we evaluated the levels of PSD-95, one of the major scaffolding protein in the excitatory postsynaptic density and a potent regulator of synaptic strength (Chen et al, 2011b), and the levels of the presynaptic component synaptophysin, which are known to be reduced in APP/PS1 mice at advanced stages of the neurodegenerative process (Woo et al, 2015;Mitew et al, 2013).…”

Hippocampal Deficits in Amyloid-β-Related Rodent Models of Alzheimer’s Disease

“…These potential diseasemodifying drugs fall into four categories: monoclonal antibodies, gamma secretase inhibitors, tau aggregation inhibitors, and symptomatic treatments. Some examples of previously failed clinical trials include (i) bapineuzumab, one of the first monoclonal amyloid-β antibodies to reach phase 3 clinical trials, but unfortunately was found to have no significant clinical benefit (Salloway et al, 2014), (ii) solanezumab, which despite demonstrating an excellent safety profile and low incidence of vasogenic edema, failed to meet primary and secondary endpoints in the phase2B-3A study (Doody et al, 2014;Siemers et al, 2016), (iii) crenezumab did not show a significant benefit in treatment in comparison to placebo in a phase 2 trial (Miller, 2012), and (iv) gantenerumab did not meet a significant clinical efficacy endpoint in phase 3 trials at its administered dosage (Ostrowitzki et al, 2017). However, more recently, Aducanumab, a human monoclonal antibody that is selective for aggregated forms of amyloid-β has been examined as a potential treatment for amyloid-β-associated pathologies.…”