Age-dependent Accumulation of Soluble Amyloid β (Aβ) Oligomers Reverses the Neuroprotective Effect of Soluble Amyloid Precursor Protein-α (sAPPα) by Modulating Phosphatidylinositol 3-Kinase (PI3K)/Akt-GSK-3β Pathway in Alzheimer Mouse Model

Abstract

Neurotrophins, activating the PI3K/Akt signaling pathway, control neuronal survival and plasticity. Alterations in NGF, BDNF, IGF-1, or insulin signaling are implicated in the pathogenesis of Alzheimer disease. We have previously characterized a bigenic PS1؋APP transgenic mouse displaying early hippocampal A␤ deposition (3 to 4 months) but late (17 to 18 months) neurodegeneration of pyramidal cells, paralleled to the accumulation of soluble A␤ oligomers. We hypothesized that PI3K/Akt/GSK-3␤ signaling pathway could be involved in this apparent age-dependent neuroprotective/neurodegenerative status. In fact, our data demonstrated that, as compared with age-matched nontransgenic controls, the Ser-9 phosphorylation of GSK-3␤ was increased in the 6-month PS1؋APP hippocampus, whereas in aged PS1؋APP animals (18 months), GSK-3␤ phosphorylation levels displayed a marked decrease. Using N2a and primary neuronal cell cultures, we demonstrated that soluble amyloid precursor protein-␣ (sAPP␣), the predominant APP-derived fragment in young PS1؋APP mice, acting through IGF-1 and/or insulin receptors, activated the PI3K/Akt pathway, phosphorylated the GSK-3␤ activity, and in consequence, exerted a neuroprotective action. On the contrary, several oligomeric A␤ forms, present in the soluble fractions of aged PS1؋APP mice, inhibited the induced phosphorylation of Akt/GSK-3␤ and decreased the neuronal survival. Furthermore, synthetic A␤ oligomers blocked the effect mediated by different neurotrophins (NGF, BDNF, insulin, and IGF-1) and sAPP␣, displaying high selectivity for NGF. In conclusion, the age-dependent appearance of APP-derived soluble factors modulated the PI3K/Akt/GSK-3␤ signaling pathway through the major neurotrophin receptors. sAPP␣ stimulated and A␤ oligomers blocked the prosurvival signaling. Our data might provide insights into the selective vulnerability of specific neuronal groups in Alzheimer disease.The molecular mechanisms underlying the selective neurodegeneration in Alzheimer disease (AD) 5 remain unclear. Amyloid-␤ (A␤) peptides, proteolytically excised from the amyloid precursor protein (APP), are considered the primary pathological agents in AD. However, their precise modes of action, toxic conformational forms, and molecular targets are still controversial (for review see Ref. 1). Transgenic mouse models, overexpressing mutated forms of human APP, are widely used to study AD pathogenesis. These models develop extensive A␤ deposition in the disease-vulnerable brain regions (such as hippocampus); however, neurons are well protected until late ages. The factors and pathways maintaining neuronal integrity at young/middle ages in these AD models and those inducing neurodegeneration in the aged animals remains to be defined.NGF, BDNF, IGF-1, and insulin are trophic factors critical for neuronal survival and plasticity, underlying memory, and learning (2-4) and could be implicated in AD development.

Regulation of Synaptic Amyloid-β Generation through BACE1 Retrograde Transport in a Mouse Model of Alzheimer's Disease

“…The constructs encoding Snapin, yellow fluorescent protein (YFP)-Rab7, and AAV9-mCherry-Snapin and AAV9-mCherry were kindly provided by Z.-H. Sheng as described previously . The purified polyclonal antibody against mouse N-terminal Snapin was described previously (Tian et al, 2005). Snapin constructs and antibody were obtained from Z.-H. Sheng.…”

“…By using the wellcharacterized A11 antibody that detects intracellular A␤ oligomers, a soluble amyloid conformation, but not APP and its cleaved products C99 (Kayed et al, 2003;Jimenez et al, 2008Jimenez et al, , 2011Zempel C) showing that elevated Snapin expression enhanced BACE1 targeting to the granule cells of dentate gyrus (soma) and thus reduced BACE1 clustering in the hippocampal mossy fibers (process) in mutant hAPP mice. BACE1 clusters, indicated by white arrows, were not readily detected in WT mouse brains.…”

“…Axonal processes were selected as we reported previously (Kang et al, 2008;Ye and Cai, 2014;Ye et al, 2015). Axons in live images were distinguished from dendrites based on known morphological characteristics: greater length, thin and uniform diameter, and sparse branching (Banker and Cowan, 1979).…”

“…Kymographs were used to trace axonal anterograde or retrograde movement of membranous organelles and to count stationary ones as described previously (Miller and Sheetz, 2004;Kang et al, 2008), with extra plugins for ImageJ. Briefly, we used the "Straighten" plugin to straighten curved axons and the "Grouped ZProjector" to z-axially project resliced time-lapsed images.…”

“…These findings raise a fundamental question: does axonal transport of BACE1 play a key role in regulating its trafficking and presynaptic localization, thus limiting APP processing at axonal terminals? Many studies focused on BACE trafficking in nonneuronal cells (Sannerud et al, 2011;Bhalla et al, 2012) or neuron-derived cell lines (Tesco et al, 2007;Kang et al, 2012). However, it remains unknown whether axonal transport regulates synaptic BACE1 trafficking.…”