The two faces of synaptic failure in App NL-G-F knock-in mice
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(2020) 12:100
RESEARCH
Open Access
The two faces of synaptic failure in AppNL-G-F knock-in mice Amira Latif-Hernandez1,2, Victor Sabanov1,3, Tariq Ahmed1,4, Katleen Craessaerts3,5, Takashi Saito6,7, Takaomi Saido6 and Detlef Balschun1,3*
Abstract Background: Intensive basic and preclinical research into Alzheimer’s disease (AD) has yielded important new findings, but they could not yet been translated into effective therapies. One of the reasons is the lack of animal models that sufficiently reproduce the complexity of human AD and the response of human brain circuits to novel treatment approaches. As a step in overcoming these limitations, new App knock-in models have been developed that avoid transgenic APP overexpression and its associated side effects. These mice are proposed to serve as valuable models to examine Aß-related pathology in “preclinical AD.” Methods: Since AD as the most common form of dementia progresses into synaptic failure as a major cause of cognitive deficits, the detailed characterization of synaptic dysfunction in these new models is essential. Here, we addressed this by extracellular and whole-cell patch-clamp recordings in AppNL-G-F mice compared to AppNL animals which served as controls. Results: We found a beginning synaptic impairment (LTP deficit) at 3–4 months in the prefrontal cortex of AppNL-G-F mice that is further aggravated and extended to the hippocampus at 6–8 months. Measurements of miniature EPSCs and IPSCs point to a marked increase in excitatory and inhibitory presynaptic activity, the latter accompanied by a moderate increase in postsynaptic inhibitory function. Conclusions: Our data reveal a marked impairment of primarily postsynaptic processes at the level of synaptic plasticity but the dominance of a presumably compensatory presynaptic upregulation at the level of elementary miniature synaptic function. Keywords: App knock-in mice, Long-term potentiation, Long-term depression, Miniature synaptic currents, Presynaptic glutamatergic and GABAergic upregulation, Electrophysiological phenotyping
Introduction There is a general consensus on two major histopathological characteristics of AD, extracellular amyloid plaques, consisting of fibrils and non-fibrillar forms of the polypeptide amyloid ß (Aß) and neurofibrillary tangles (NFTs), and intracellular aggregates that are composed of hyperphosphorylated forms of the tau protein [1]. Aß * Correspondence: [email protected] 1 Brain and Cognition, KU Leuven, Tiensestraat 102, Box 3714, 3000 Leuven, Belgium 3 Leuven Brain Institute, KU Leuven, Leuven, Belgium Full list of author information is available at the end of the article
originates from the sequential endoproteolytic cleavage of amyloid precursor protein (APP) resulting in several forms of Aß of which the 42-residue Aß42 has the strongest propensity to form aggregates and the highest cellular toxicity [2–4]. The discovery of genetically inherited, early-onset, familial forms of AD (FAD) in the 1990s of the last century made Aß the primary focus of AD rese
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