Aβ/Amyloid Precursor Protein-Induced Hyperexcitability and Dysregulation of Homeostatic Synaptic Plasticity in Neuron Models of Alzheimer’s Disease

Abstract

Alzheimer’s disease (AD) is increasingly seen as a disease of synapses and diverse evidence has implicated the amyloid-β peptide (Aβ) in synapse damage. The molecular and cellular mechanism(s) by which Aβ and/or its precursor protein, the amyloid precursor protein (APP) can affect synapses remains unclear. Interestingly, early hyperexcitability has been described in human AD and mouse models of AD, which precedes later hypoactivity. Here we show that neurons in culture with either elevated levels of Aβ or with human APP mutated to prevent Aβ generation can both induce hyperactivity as detected by elevated calcium transient frequency and amplitude. Since homeostatic synaptic plasticity (HSP) mechanisms normally maintain a setpoint of activity, we examined whether HSP was altered in AD transgenic neurons. Using methods known to induce HSP, we demonstrate that APP protein levels are regulated by chronic modulation of activity and that AD transgenic neurons have an impaired adaptation of calcium transients to global changes in activity. Further, AD transgenic compared to WT neurons failed to adjust the length of their axon initial segments (AIS), an adaptation known to alter excitability. Thus, we show that both APP and Aβ influence neuronal activity and that mechanisms of HSP are disrupted in primary neuron models of AD.

ProSAAS is Preferentially Secreted from Neurons During Homeostatic Scaling and Reduces Amyloid Plaque Size in the 5xFAD Mouse Hippocampus

“…Homeostatic scaling is necessary to maintain synaptic function within a physiological limit; thus, this scaling capability is of great interest in the context of neurodegenerative diseases such as AD (4). As AD progresses, accumulation of toxic amyloid oligomers in the hippocampus results in altered thresholds for LTP and LTD; synapse loss; and impairment of homeostatic scaling (6,29,30). As mentioned above, proSAAS functions as an amyloid anti-aggregant, both in vitro as well as in cell models of amyloid toxicity (12), and has been shown to bind amyloid (12,21).…”

“…Homeostatic mechanisms become defective in neurons expressing AD-related transgenes, as these neurons are unable to compensate for disruptions in network activity (6). The inability of neurons to constrain neuronal firing within a physiological limit leads to excessive strengthening or weakening of synapses, and eventually, neurological disorders (reviewed in (4)).…”

Galectin-3 shapes toxic alpha-synuclein strains in Parkinson’s disease

“…Primary neuronal cultures were established following the ethical guidelines and approved by the Lund University Ethical committee (M46-16). Primary neurons were isolated from WT mouse embryos on embryonic day 16, as described before [ 40 ], 2000 cells per well were seeded on a 96-well plate pre-coated with poly-d-lysine (Sigma Aldrich) and then rinsed in autoclaved distilled water. Cell suspensions were plated in Dulbecco’s modified Eagle medium (DMEM) (Thermo Fisher Scientific) containing 10% FBS and 1% penicillin–streptomycin; after 3–5 h, media were exchanged for FBS-free complete Neurobasal medium (Gibco, Thermo Fisher Scientific).…”

Homeostatic plasticity of axonal excitable sites in Alzheimer's disease

“…Alterations in the AIS structure may be mediated by APP overexpression or soluble Aβ rather than, or in addition to, Aβ plaque toxicity. In cortical and hippocampal APP/PS1 primary neurons (where APP and soluble Aβ levels, but not plaques, is expected to be high), AISs were shorter than in wild-type (WT) mice and were not responsive to homeostatic changes in AIS length usually triggered by increasing (with bicuculline) or decreasing (with TTX) neuronal activity (Martinsson et al, 2022 ). Alternatively, applying soluble Aβ onto cultured hippocampal neurons impaired microtubule plus-end-binding protein 3 (EB3) stability at the AIS, thereby disturbing microtubule integrity and lengthening the AIS, and was accompanied by a depolarising shift in the AP voltage threshold (Tsushima et al, 2015 ).…”