Time-dependent reversal of synaptic plasticity induced by physiological concentrations of oligomeric Aβ42: an early index of Alzheimer’s disease

Abstract

The oligomeric amyloid-β (Aβ) peptide is thought to contribute to the subtle amnesic changes in Alzheimer’s disease (AD) by causing synaptic dysfunction. Here, we examined the time course of synaptic changes in mouse hippocampal neurons following exposure to Aβ42 at picomolar concentrations, mimicking its physiological levels in the brain. We found opposite effects of the peptide with short exposures in the range of minutes enhancing synaptic plasticity, and longer exposures lasting several hours reducing it. The plasticity reduction was concomitant with an increase in the basal frequency of spontaneous neurotransmitter release, a higher basal number of functional presynaptic release sites, and a redistribution of synaptic proteins including the vesicle-associated proteins synapsin I, synaptophysin, and the post-synaptic glutamate receptor I. These synaptic alterations were mediated by cytoskeletal changes involving actin polymerization and p38 mitogen-activated protein kinase. These in vitro findings were confirmed in vivo with short hippocampal infusions of picomolar Aβ enhancing contextual memory and prolonged infusions impairing it. Our findings provide a model for initiation of synaptic dysfunction whereby exposure to physiologic levels of Aβ for a prolonged period of time causes microstructural changes at the synapse which result in increased transmitter release, failure of synaptic plasticity, and memory loss.

An exploratory clinical study of p38α kinase inhibition in Alzheimer's disease

“…The effect we found on episodic memory is in line with a broad scientific literature that indicates that p38 α in involved in oligomeric amyloid‐beta and inflammation‐induced synaptic dysfunction and to stress‐ and age‐related synaptic dysfunction in the hippocampus 4, 5, 10, 11, 12, 13, 14, 31. In our clinical study, the ES that we saw for immediate and delay recall compares favorably to ES of ≤0.2 for WMS immediate or delayed recall at week 12 in the placebo‐treated subjects in two trials of Souvenaid in a similar patient population (mild AD, baseline MMSE = 24) 32, 33.…”

“…Traditionally p38 α kinase is considered to be an inflammation‐related target as microglial p38 α promotes production of proinflammatory cytokines6 and modulates microglial activation state,7, 8 and in the healthy state p38 α expression within neurons is low 9. However, more recent findings indicate that neuronal p38 α is increased in disease and under stress, and neuronal p38 α expression has been implicated in amyloid‐beta and/or inflammation‐induced synaptic dysfunction,10, 11, 12, 13, 14 specifically impaired synaptic plasticity. Consistent with the biology of neuronal p38 α , selective small molecule inhibitors of p38 α rapidly (i.e., within 2–3 weeks) reverse spatial learning defects in the APP/PS1 mouse model,15 aged rats16 and in tauopathy (hTau) mouse model 17…”

NGF steers microglia toward a neuroprotective phenotype

“…High concentrations of Aβ or Aβ oligomers inhibit synaptic plasticity processes (Selkoe, ; Shankar et al, ; Walsh et al, ). Aβ has proven to be a key player in synaptic plasticity also at physiological concentrations: while short exposure with low concentrations of the peptide actually enhance synaptic plasticity, longer exposures lasting several hours reduce it (Koppensteiner et al, ). This underlines the importance of the homeostasis of Aβ levels and processing in the brain, and thus of microglia themselves as an important factor in its clearance.…”

Early compensatory responses against neuronal injury: A new therapeutic window of opportunity for Alzheimer's Disease?

“…Based on animal and in vitro studies using sub‐lethal concentrations of A β for slow development of neuronal damage, early improvements in synaptic plasticity and memory were proposed to be mediated by an increased rate of neurotransmitter release. With time, however, this would be responsible for excitotoxic damage and decline of these functions …”

“…With time, however, this would be responsible for excitotoxic damage and decline of these functions. 48 Unexpectedly, several molecules not exclusively linked to neuronal activation, also show a biphasic pattern of expression during disease progression. For example, in presymptomatic AD mouse models, a compensatory mechanism acts through upregulation of nitric oxide (NO) synthase and recruitment of NO.…”