Abstract
Alzheimer’s disease (AD) is the most common form of dementia. Even though most AD cases are sporadic, a small percentage is familial due to autosomal dominant mutations in amyloid precursor protein (APP), presenilin-1 (PSEN1), and presenilin-2 (PSEN2) genes. AD mutations contribute to the generation of toxic amyloid β (Aβ) peptides and the formation of cerebral plaques, leading to the formulation of the amyloid cascade hypothesis for AD pathogenesis. Many drugs have been developed to inhibit this pathway but all these approaches currently failed, raising the need to find additional pathogenic mechanisms. Alterations in cellular calcium (Ca2+) signaling have also been reported as causative of neurodegeneration. Interestingly, Aβ peptides, mutated presenilin-1 (PS1), and presenilin-2 (PS2) variously lead to modifications in Ca2+ homeostasis. In this contribution, we focus on PS2, summarizing how AD-linked PS2 mutants alter multiple Ca2+ pathways and the functional consequences of this Ca2+ dysregulation in AD pathogenesis.
Highlights
Alzheimer’s disease (AD) is an age-related neurodegenerative disorder, considered the most common cause of dementia
Studies in fibroblasts from asymptomatic Familial AD (FAD)-PS patients reported an increased IP3-mediated Ca2+ release from the endoplasmic reticulum (ER) [127,128]. These studies lay the groundwork for the formulation of the “Ca2+ overload” hypothesis for AD that sustains that FAD-linked PS mutations, by increasing ER Ca2+ content, cause excessive Ca2+ release in the cytosol, altering amyloid precursor protein (APP) processing, increasing neuronal sensitization to amyloid β (Aβ) and producing cytotoxic stimuli that eventually lead to a Ca2+-dependent cell death [130]
The analysis indicates that FAD-linked PS2 mutations decrease the Ca2+ content of the medial-Golgi Apparatus (GA), without affecting the trans-GA [153] (Figure 1), extending the results obtained earlier employing an aequorin Ca2+ probe targeted to the whole GA [148]
Summary
As its discovery in 1987, the functions of APP and its cleavage products have been subjected to intense investigations stimulated by the seminal finding that 40/42 amino acid fragments of APP, called Aβ peptides, are abundant in brain amyloid plaques of AD patients. APP overexpression in transgenic (tg) mice increases spine density, alters LTP responses and performance in the Morris water maze, reduces brain weight, induces defects in both axonal growth/white matter and axonal transport [32] Taken together, these data support a role for APP in cellular growth and apoptosis, synapse formation, and maintenance and in neuronal migration in early embryogenesis, by itself or in association with other intracellular proteins (reviewed in [33,34]). It is worth mentioning that FAD-APP mutations are mainly localized near the sites of secretase cleavage, promoting the amyloidogenic pathway These considerations, together with the fact that mutations inside the Aβ peptide sequence favor its aggregation, and that APP overexpression (e.g., in Down Syndrome, due to trisomy 21) is associated with EOAD symptoms, give strong genetic support to the amyloid cascade hypothesis for AD pathogenesis. It has been proposed that Aβ soluble oligomers, and not the insoluble fibrils, are the toxic forms causing synaptic dysfunctions [47]
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