Influences de l'homéostasie calcique neuronale sur le métabolisme des protéines impliquées dans la maladie d'Alzeimer
(2007)
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- Authors
- Supervisors
- Octave, Jean-Noël
- Abstract
- Alzheimer's disease (AD), the most frequent cause of dementia, is characterized by the presence of two neuropathological lesions: accumulation of b-amyloid (Ab) peptides in extracellular senile plaques and neurofibrillary tangles containing hyperphosphorylated protein tau. Ab is generated by the sequential cleavage of its precursor, the amyloid precursor protein (APP), performed by BACE and the g-secretase complex containing presenilin 1, Nicastrin, PEN-2 and APH-1. Tau is a microtubule-associated protein known as a developmentally regulated neuronal phosphoprotein. Calcium signaling is a central process in brain function and its destabilization seems to be central to the pathogenesis of AD. Disruption of cellular calcium homeostasis is also reported to increase age-associated impairments in learning and memory. During aging, changes observed in neuronal calcium buffering processes and activation of calcium voltage-dependent channels support the calcium hypothesis in the development of AD. To investigate the influence of the imbalance of intracellular calcium homeostasis on the APP metabolism, rat cortical neurons infected with human APP were depolarized in presence of extracellular potassium. We report that an influx of extracellular calcium favors the amyloidogenic processing of human APP by increasing the production of intraneuronal C-terminal fragments produced by the b-cleavage of the protein (CTFb). The increase of intracellular calcium levels triggers the specific accumulation of neurotoxic intraneuronal Ab1-42. These effects were completely reversed by nimodipine, an antagonist of L-type calcium channels. Therefore, the release of calcium-store content in the endoplasmic reticulum is not sufficient to induce the production of intraneuronal Ab, but the capacitive calcium entry mechanism, which is a process for replenishing depleted calcium stores in the endoplasmic reticulum, is needed to trigger its accumulation. APP is known to be phosphorylated in its short intracellular cytoplasmic domain on several sites. Among them, only the threonine 668 (Thr668) residue has received particular attention Indeed, the phosphorylation status of this residue seems to be closely linked with the production of Ab. Moreover, glycogen synthase kinase-3b and cyclin-dependent kinase 5 are known to phosphorylate APP on Thr668 and both are thought to regulate the production of Ab in neural cells. These kinases are not only known to regulate the amyloidogenic pathway of APP, but they also play a role in diverse array of cellular functions including cell adhesion, cell division and tau phosphorylation. Since deregulation of calcium homeostasis induced by neuronal depolarization may play an important role in intraneuronal Ab1-42 production, we have investigated the influence of an extracellular calcium influx on the phosphorylation of human APP and endogenous tau in rat cortical neurons. We have analyzed the time course of APP and tau phosphorylations after disrupting neuronal calcium homeostasis by K+-induced depolarization. We report that high cytosolic calcium concentrations induce a transient increase in both APP and tau phosphorylation. Moreover, the transient phosphorylation of APP on Thr668 induces the progressive accumulation of neurotoxic intraneuronal Ab1-42. For the first time, we report that a disruption of cellular calcium homeostasis, induced by neuronal depolarization, triggers the two major processes responsible of the formation of the two typical pathological lesions found in AD brains. Thus, calcium deregulation is a crucial event of AD pathogenesis, and elicits the characteristic lesions of this disorder, including increased Ab formation, hyperphosphorylation of tau and neuronal cell death.
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Citations
Pierrot, N. (2007). Influences de l’homéostasie calcique neuronale sur le métabolisme des protéines impliquées dans la maladie d’Alzeimer. https://hdl.handle.net/2078.5/112122