Abstract
In early Alzheimer disease (AD) models synaptic failures and upstreaming aberrant patterns of network synchronous activity result in hippocampal-dependent memory deficits. In such initial stage, soluble forms of Amyloid-β (Aβ) peptides have been shown to play a causal role. Among different Aβ species, Aβ25–35 has been identified as the biologically active fragment, as induces major neuropathological signs related to early AD stages. Consequently, it has been extensively used to acutely explore the pathophysiological events related with neuronal dysfunction induced by soluble Aβ forms. However, the synaptic mechanisms underlying its toxic effects on hippocampal-dependent memory remain unresolved. Here, in an in vivo model of amyloidosis generated by intracerebroventricular injections of Aβ25–35 we studied the synaptic dysfunction mechanisms underlying hippocampal cognitive deficits. At the synaptic level, long-term potentiation (LTP) of synaptic excitation and inhibition was induced in CA1 region by high frequency simulation (HFS) applied to Schaffer collaterals. Aβ25–35 was found to alter metaplastic mechanisms of plasticity, facilitating long-term depression (LTD) of both types of LTP. In addition, aberrant synchronization of hippocampal network activity was found while at the behavioral level, deficits in hippocampal-dependent habituation and recognition memories emerged. Together, our results provide a substrate for synaptic disruption mechanism underlying hippocampal cognitive deficits present in Aβ25–35 amyloidosis model.
Highlights
Alzheimer’s disease (AD), the most prevalent neurodegenerative disorder, is characterized by progressive memory loss together with the presence of extracellular amyloid plaques, composed of Biology 2020, 9, 175; doi:10.3390/biology9070175 www.mdpi.com/journal/biologyBiology 2020, 9, 175 amyloid-β (Aβ), and of intracellular neurofibrillary tangles, composed of hyperphosphorylated tau [1].The causal role of Aβ in the disease has been widely reported in multiple in vivo and in vitro models of early amyloidosis
We show that icv. administration of Aβ25–35 resulted in an alteration of the metaplastic mechanisms that modulate synaptic plasticity threshold induction in the dorsal hippocampus, facilitating long-term depression (LTD) instead of long-term potentiation (LTP)
As the hippocampal network activity is known to have a critical role in learning and memory processes altered in Alzheimer disease (AD) [32], we examined whether our model of amyloidosis exhibited impairments in oscillatory rhythms in alert mice
Summary
Alzheimer’s disease (AD), the most prevalent neurodegenerative disorder, is characterized by progressive memory loss together with the presence of extracellular amyloid plaques, composed of Biology 2020, 9, 175; doi:10.3390/biology9070175 www.mdpi.com/journal/biology. The causal role of Aβ in the disease has been widely reported in multiple in vivo and in vitro models of early amyloidosis. Evidence has shown that the progressive accumulation of Aβ has a causal role in AD, it is clear that misfolded oligomeric forms or small Aβ aggregates, and not necessarily plaque formation, are critical in the initial state of synaptic dysfunction in early AD development [3,4]. The degree of cognitive deficits observed in early AD correlates better with Aβ assayed biochemically, than with synapse loss, plaque accumulation, tangle formation, or neurodegeneration [4,6]
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