Control of neuronal calcium homeostasis by the Amyloid Precursor Protein
(2010)
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- Abstract
- (en) Alzheimer disease (AD) is a devastating neurodegenerative disorder that concerns up to one third of the elderly population. AD major symptom is memory impairment, followed by a very progressive decline of other cognitive functions. Intense research efforts and multiple models for AD provided evidence for alterations in the plasticity of synaptic transmission. These alterations, probably generating memory impairments, are partially mediated by neurotoxic soluble Aβ peptides. Another cause for the synaptic failure is the early disruption of calcium homeostasis, compromising neuronal calcium signaling. Aggregated Aβ peptides constitute the core of senile plaques which accumulate in brains of AD patients. Aβ derives from the amyloidogenic processing of a protein called amyloid precursor protein (APP). Although the metabolism of APP has been intensively studied, the function of this protein remains unclear. Among other putative functions, APP or its derivates may participate in the control of calcium homeostasis. In this work, we investigated the influence of human APP expression on neuronal calcium homeostasis in rat cortical neurons. Cultured cortical neurons have spontaneous synaptic activity that generates synchronous calcium oscillations throughout the network. We could demonstrate that hAPP expression completely abolishes calcium oscillations, by lowering neuronal excitability. hAPP expression increases L-type voltage-dependent calcium currents, which, in turn, activate calcium-dependent K+ channels (SK channels). This leads to an increase of the medium afterhyperpolarization phase (mAHP) that follows action potentials, thus decreasing the intrinsic excitability of hAPP-expressing neurons. On the other hand, reducing endogenous levels of APP increases the frequency and reduces the amplitude of calcium oscillations. We also observed that phosphorylation of T668, located in the intracellular domain of APP, was crucial for hAPP-mediated abolition of calcium oscillations. Inhibition of hAPP phosphorylation using inhibitors of JNK and GSK3 protein kinases, resulted in the recovery of calcium oscillations in a hAPP-expressing network. The importance of T668 phosphorylation was confirmed by the expression of a mutated, non-phosphorylable form of APP (hAPPT668A). Expression of hAPPT668A did not inhibit calcium oscillations. Furthermore, amounts of hAPPT668A at the cell surface were reduced by 50%, when compared to hAPP, indicating that appropriate trafficking of hAPP could be involved in the control of neuronal excitability. Finally, we report that the expression of a hAPP construct lacking the intracellular domain (hAPP∆C) abnormally increases calcium currents, independently of the L-type component. This suggests a global control of voltage-dependent calcium currents by the intracellular domain of APP. Together, these results indicate a new role of APP in the regulation of intrinsic neuronal excitability, mediated by the control of voltage-dependent calcium currents.
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Citations
Ferrao Santos, S. (2010). Control of neuronal calcium homeostasis by the Amyloid Precursor Protein. https://hdl.handle.net/2078.5/130645