Alzheimer Amyloid β‐Peptide A‐β_25‐35 Blocks Adenylate Cyclase‐Mediated Forms of Hippocampal Long‐Term Potentiation

Abstract

Progressive memory loss and deposition of amyloid beta (Abeta) peptides throughout cortical regions are hallmarks of Alzheimer's disease (AD). Several studies in mice and rats have shown that overexpression of amyloid precursor protein (APP) or pretreatment with Abeta peptide fragments results in the inhibition of hippocampal long-term potentiation (LTP) as well as impairments in learning and memory of hippocampal-dependent tasks. For these studies we have investigated the effects of the Abeta(25-35) peptide fragment on LTP induced by adenylate cyclase stimulation followed immediately by application of Mg(++)-free aCSF ("chemLTP"). Treatment of young adult slices with the Abeta(25-35) peptide had no significant effect on basal synaptic transmission in area CA1, but treatment with the peptide for 20 min before inducing chemLTP with isoproterenol (ISO; 1 microM) or forskolin (FSK;10 microM) + Mg(++)-free aCSF resulted in complete blockade of LTP. In contrast, normal ISO-chemLTP was observed after treatment with the control peptide Abeta(35-25). The ability of the Abeta(25-35) peptide fragment to block this and other forms of synaptic plasticity may help elucidate the mechanisms underlying hippocampal deficits observed in animal models of AD and/or AD individuals.

Amyloid Aβ25-35 Aggregates Say ‘NO’ to Long-Term Potentiation in the Hippocampus through Activation of Stress-Induced Phosphatase 1 and Mitochondrial Na+/Ca2+ Exchanger

“…In accordance with these data, we revealed the decreased PPF ratio at 30–100 ms interstimulus intervals in the Aβ 25-35 -treated hippocampal slices ( Figure 1 E). Furthermore, 1 h incubation of slices in the presence of 50 nM Aβ 25-35 disrupted the late LTP phase, 3 h after the tetanic stimulation ( Figure 1 A,B), which was previously shown for the different stimulations’ protocols of invertebrates and mammal species [ 7 , 51 , 52 , 53 ]. Curiously, the Aβ 25-35 monomers in the freshly prepared amyloid solution (50 nM) did not change the LTP kinetics, after tetanic stimulation of the Aβ 25-35 -pretreated hippocampal slices ( Supplementary Figure S5 ).…”

Amyloid-β Decreases Nitric Oxide Production in Cultured Retinal Neurons: A Possible Mechanism for Synaptic Dysfunction in Alzheimer’s Disease?

“…Because synaptic dysfunction and inhibition of LTP appear to be early events in Ab-induced neuronal pathology [26,27,[57][58][59][60], the decrease in NO production induced by Ab could represent a mechanistic link with synaptic failure and with cholinergic impairment in early AD.…”

Noradrenergic gating of long-lasting synaptic potentiation in the hippocampus: from neurobiology to translational biomedicine

“…Animal models of AD often express impaired hippocampal LTP and defective hippocampus-dependent memory (for instance, Li et al, 2017;Liu et al, 2008), and some evidence suggests that noradrenergic supplementation can improve memory in such models (Rorabaugh et al, 2017). Because AD pathology in the hippocampus blocks generation of adenylyl-cyclase mediated LTP (Bisel, Henkins, & Parfitt, 2007) and impairs expression of synaptic tagging/capture (Li et al, 2017), it is possible that disruption in b-AR modulation of synaptic state could decrease the likelihood of robust long-term memory in this disorder. Significant LC neural loss also occurs in Parkinson's disease (PD), but the contribution of noradrenergic hippocampal synaptic plasticity to PD's cognitive and mood symptoms remains to be fully explored (Weinshenker, 2018).…”