Free Content Presenilins, Deranged Calcium Homeostasis, Synaptic Loss and Dysfunction in Alzheimer's Disease

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Abstract:

Alzheimer's disease (AD) is the most common age-related neurodegenerative disorder affecting millions of people. Synaptic dysfunction and physical loss of synapses are responsible for memory impairments in AD. The molecular mechanisms responsible for synaptic loss in AD are not understood. The main risk factor for sporadic AD (SAD) is advanced age. Missense mutations in presenilin (PS) proteins and in amyloid precursor protein (APP) are responsible for majority of rare familial AD (FAD) cases. Increased production of A 42 amyloidogenic peptide occurs in SAD and FAD. Synaptotoxic effects of A 42 may be linked to synaptic loss in AD. FAD mutations in PS proteins disrupt endoplasmic reticulum (ER) calcium (Ca2+) leak function of PSs and result in increased Ca2+ levels in neuronal ER. Similar increases in neuronal ER Ca2+ levels occur in aging neurons. Increased neuronal ER Ca2+ levels lead to a compensatory upregulation of ER Ca2+ release channels, the ryanodine receptors (RyanR), and downregulation of the synaptic store-operated Ca2+ entry (SOC) pathway. In this review we propose a hypothesis that excessive Ca2+ release from the ER and insufficient SOC Ca2+ entry lead to destabilization and eventual elimination of mature mushroom spines in PS-FAD neurons and in aging SAD neurons. The proposed Ca2+-dependent spine destabilization mechanism may act in parallel or synergistically with A 42 synaptotoxicity mechanisms. The proposed model may help to establish a cause-and-effect connection between abnormal Ca2+ and amyloid homeostasis and synaptic loss in AD.

Keywords: ALZHEIMER'S DISEASE; AMYLOID HYPOTHESIS; CALCIUM HYPOTHESIS; DYSFUNCTION; PRESENILINS; SYNAPTIC LOSS

Document Type: Review Article

DOI: http://dx.doi.org/10.1166/msr.2012.1002

Publication date: June 1, 2012

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  • The MESSENGER is an international peer-reviewed journal, focused on all aspects of messenger-signaling. The MESSENGER is devoted to all aspects of messenger- signaling, from the upstream activation of the receptors of the first messengers to the downstream signaling cascades. Undoubtedly, more novel second messengers will be discovered, expanding the scope of the journal appropriately. The MESSENGER publishes review articles, full research articles and short communications of important new scientific findings on all research aspects of messengers.
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