Expression of Human Amyloid Precursor Protein in Rat Cortical Neurons Inhibits Calcium Oscillations

Abstract

Synchronous calcium oscillations are observed in primary cultures of rat cortical neurons when mature networks are formed. This spontaneous neuronal activity needs an accurate control of calcium homeostasis. Alteration of intraneuronal calcium concentration is described in many neurodegenerative disorders, including Alzheimer disease (AD). Although processing of amyloid precursor protein (APP) that generates A␤ peptide has critical implications for AD pathogenesis, the neuronal function of APP remains unclear. Here, we report that expression of human APP (hAPP) in rat cortical neurons increases L-type calcium currents, which stimulate SK channels, calcium-dependent K ϩ channels responsible for medium afterhyperpolarization (mAHP). In a neuronal network, increased mAHP in some neurons expressing hAPP leads to inhibition of calcium oscillations in all the cells of the network. This inhibition is independent of production and secretion of A␤ and other APP metabolites. In a neuronal network, reduction of endogenous APP expression using shRNA increases the frequency and reduces the amplitude of calcium oscillations. Altogether, these data support a key role for APP in the control of neuronal excitability.

Nebula/DSCR1 Upregulation Delays Neurodegeneration and Protects against APP-Induced Axonal Transport Defects by Restoring Calcineurin and GSK-3β Signaling

“…First, we find that APP upregulation elevated intracellular calcium level and calcineurin activity, and that restoring calcineurin activity to normal suppressed the synaptotagmin aggregate accumulation in axons. The observed increase in calcium and calcineurin activity is consistent with reports of calcium dyshomeostasis and elevated calcineurin phosphatase activity found in AD brains [78]–[80], as well as reports demonstrating elevated neuronal calcium level due to APP overexpression and increased calcineurin activation in Tg2576 transgenic mice carrying the APP swe mutant allele [81], [82]. Second, APP upregulation resulted in calcineurin dependent dephosphorylation of GSK-3β at Ser9 site, a process thought to activate GSK-3β kinase [56].…”

Unfolded Protein Response and PERK Kinase as a New Therapeutic Target in the Pathogenesis of Alzheimer’s Disease

“…Mutations in the APP gene are known as calcium oscillations due to reduction in APP translocation to the outer membrane. Moreover, the high concentration of calcium in the cell cytosol, which is a specific hallmark of AD, leads to the attenuation of non-amyloidogenic cleavage of APP by secretase α and as a result, aggregation of the neurotoxic variant of Aβ 42 [55, 56]. Moreover, Aβ molecules may contribute to release of calcium ions into the cytoplasm from ER stories [57].…”

Physiological Functions of APP Family Proteins

“…APP-KO mice showed increased levels of Ca V 1.2 channels in the striatum that lead to alterations in GABAergic short term plasticity in striatal and hippocampal neurons, such as reduced GABAergic paired pulse inhibition and increased GABAergic posttetanic potentiation ). Moreover, there is recent evidence from overexpression and APP knockdown studies in hippocampal neurons indicating an Ab independent role of APP for the regulation of Ca 2þ -oscillations (Santos et al 2009). …”