Search

Bidirectional relationship of calcium homeostasis and APP processing in Alzheimer's disease Alzheimer's disease is the most common primary cause of dementia worldwide. Neuropathologically, the disease is characterized by the deposition of amyloid-ß in amyloid plaques as well as neurofibrillary tangles. Neurofibrillary tangles are formed during hyperphosphorylation of tau. Aß generated by amyloidogenic processing of the Alzheimer's precursor protein APP, primarily by the cleavages of ß- and γ-secretase. In contrast, in the non-amyloidogenic processing pathway, no Aß is formed by the α-secretase cleavage followed by the γ-secretase cleavage, but the peptide p3 is generated instead. Alzheimer's disease is a multifactorial disorder that may be associated with an impaired calcium homeostasis. Calcium dysregulation appears to be a very early event in AD pathogenesis. Improved understanding of the regulatory processes can contribute to further research into the disease. The basal calcium current in the largest calcium store of the cell, the endoplasmic reticulum, is mainly regulated by SOCE (store operated Ca2+-entry). The calcium sensor STIM (stromal interaction molecul) interacts with Orai in the plasma membrane and the Crac channel (calcium release-activated channel) is formed. Cell models were generated with a knockout of STIM1 and STIM2 to study the influence of STIM on α-, ß- and γ-secretases. In addition, analysis of gene expression of Orai and STIM in relation to age, Braak status, and Aß content was performed in post-mortem brain samples from Alzheimer's disease patients. Supplementary, the effect of APP and APP processing products on gene expression of FMR1 and FMR2 was investigated. Both genes encode an mRNA-binding protein involved in synaptic plasticity. SOCE appears to have a regulatory effect on Aß production via γ-secretase. Here, STIM proteins would exert an enhancing effect on gene expression of components of γ-secretase as well as APP, presumably indirectly via regulation of the calcium current. Gene expression of IDE, an Aß-degrading protein, appears to be decreased. Compensatory to the increased Aß, a decreased activity of γ-secretase can be observed. With a stronger activation of SOCE, by incubation with thapsigargin, an increase of γ-secretase activity can be recorded. An effect of STIM on BACE does not appear to be present under the conditions of the present work. The effect of STIM on α-secretase cannot be clearly elucidated and may be explained by an increased turnover of α-CTF by γ-secretase In post mortem brain samples, an increase in gene expression of Orai1, Orai2, Orai3, and STIM1 and STIM2 can be proven. A positive correlation with age is present for all genes in the simultaneous presence of an increased Braak status. There is also a positive correlation with Aß content for Orai1 and Orai3 as well as both STIM proteins.Fragile X mental retardation protein FMRP is an RNA-binding protein and participates in neuronal plasticity, which is impaired in both Alzheimer's disease and fragile X syndrome. FMRP interacts with APP and leads to higher Aß levels. In the context of this work, it was demonstrated that FMRP can be affected by processing products of APP. The gene regulatory AICD appears to have an inhibitory effect on FMR2. Both calcium and FMRP contribute to memory formation by regulating protein biosyntheses of synaptic structures.