Block of Long-Term Potentiation by Naturally Secreted and Synthetic Amyloid β-Peptide in Hippocampal Slices Is Mediated via Activation of the Kinases c-Jun N-Terminal Kinase, Cyclin-Dependent Kinase 5, and p38 Mitogen-Activated Protein Kinase as well as Metabotropic Glutamate Receptor Type 5

Abstract

The mechanisms of action of human synthetic and naturally secreted cell-derived amyloid ␤-peptide (A␤) 1-42 on the induction of long-term potentiation (LTP) were investigated in the medial perforant path to dentate granule cell synapses in hippocampal slices.

Amyloid precursor protein and amyloid β-peptide bind to ATP synthase and regulate its activity at the surface of neural cells

“…Extracellular acidosis may lead to activation of the c-Jun N-terminal kinase, 74 which has been shown to mediate the inhibitory effects of Ab on LTP. 75 Also, it has been shown that exocytosed protons, resulting in acidification of the synaptic cleft, transiently suppress Ca 2 þ currents in mammalian cone photoreceptors. 76 Extracellular Ab could lead to an inhibition of Ca 2 þ currents perhaps by inducing an extracellular acidosis in the synaptic cleft and resulting in an impairment of LTP and thus to an important aspect of learning and memory dysfunction as found in Alzheimer's disease pathology.…”

Preparation and characterization of toxic Aβ aggregates for structural and functional studies in Alzheimer's disease research

“…This suggests that the physiological process of amyloid formation can be recapitulated in vitro and highlights Several studies using familial AD (fAD) mutations in animal models and cell culture experiments strongly support the notion that early intermediates in the fibrillization process (i.e., oligomers, including protofibrils) are the primary toxic Aβ species and have a central role in AD pathogenesis. This hypothesis is supported by (i) the lack of a clear correlation between fibrillar amyloid burden in AD patients and cognitive impairment 29,30 , whereas such a correlation has been reported for the soluble pool of Aβ (monomers and oligomers including protofibrils) and AD severity 31,32 ; (ii) the fact that autosomal dominant mutations in APP or its cleaving enzymes (presenilins), which favor increased production of Aβ42 and/or accumulation of protofibrils, are associated with the development of fAD [33][34][35][36] ; (iii) the indication that transgenic animals overexpressing fAD mutations in APP exhibit learning deficits and lower performance in memory tasks, compared with control animals, long before the appearance of amyloid plaques 37,38 ; (iv) the fact that intracerebral administration of soluble Aβ oligomers in live animals impairs cognitive performance and inhibits long-term potentiation (LTP), a cellular model of memory formation 19 , and induces widespread plaque pathology 39 ; and (v) the observation that treating cultured neurons with Aβ protofibrils results in impairment of ion channelss 40,41 , inhibition of LTP 42 , loss of synapses and cell death 14 . Finally, anti-Aβ antibodies specifically targeting oligomers, including protofibrils, block neurotoxicity in cultured neurons 43 and reverse behavioral deficits in mice 44 .…”

Critical role of cPLA2 in Aβ oligomer-induced neurodegeneration and memory deficit

“…This latter 85-kDa enzyme, which is also referred to as GIVA-PLA 2 (Schaloske and Dennis, 2006), is activated and translocated to membranes after calcium influx and phosphorylation by mitogen-activated protein (MAP) kinases or other kinases (Clark et al, 1995). Activation of MAP kinases and perturbation of calcium homeostasis are well known to be involved in the deleterious effects of A␤ oligomers (Small, 2009;Wang et al, 2004). We previously reported that soluble A␤ oligomers caused early calcium-dependent release of AA associated with a transient relocalization of cPLA 2 to the plasma membrane, suggesting that activation of cPLA 2 and subsequent release of AA are critical steps for soluble A␤ oligomermediated apoptosis in cortical neurons.…”