Abstract: The familial Alzheimer's disease gene products, presenilin-1 and presenilin-2 (PS1 and PS2), are involved in amyloid β-protein precursor processing (AβPP), Notch receptor signaling, and programmed cell death. However, the molecular mechanisms by which presenilins regulate these processes remain unknown. Clues about the function of a protein can be obtained by seeing whether it interacts with another protein of known function. Using the yeast two-hybrid system, we identified two proteins that interact and colocalize with the presenilins. One of these newly detected presenilin-interacting proteins belongs to the FtsH family of ATP-dependent proteases, and the other one belongs to Rhomboid superfamily of…membrane proteins that are highly conserved in eukaryotes, archaea and bacteria. Based on the pattern of amino acid residues conservation in the Rhomboid superfamily, we hypothesize that these proteins possess a metal-dependent enzymatic, possibly protease activity. The two putative proteases interacting with presenilins could mediate specific proteolysis of membrane proteins and contribute to the network of interactions in which presenilins are involved.
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Abstract: The amyloid ß protein precursor (AßPP) is sequentially processed by ß- and γ-secretases to generate the Aß peptide. The biochemical path leading to Aß formation has been extensively studied since extracellular aggregates of amyloidogenic forms of Aß peptide (Aß42) are considered the culprit of Alzheimer's disease. Aside from its pathological relevance, the biological role of AßPP proteolysis is unknown. Although never previously described, cleavage of AßPP by γ-secretase should release, together with Aß, a COOH-terminal AßPP Intracellular Domain, herein termed AID. We have now identified AID-like peptides in brain tissue of normal control and patients with sporadic Alzheimer's disease and…demonstrate that AID acts as a positive regulator of apoptosis. Thus, overproduction of AID may add to the toxic effect of Aß42 aggregates and further accelerate neurodegeneration.
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Abstract: A series of evidences suggests that enhanced susceptibility to programmed cell death (PCD) is a major pathogenetic factor in Alzheimer's disease (AD). We investigated this issue, analyzing amyloid β-protein (Aβ) production in a model of neuronal PCD, induced by staurosporine in a murine neuroblastoma cell line. When PCD was induced, a 280–290% secreted Aβ occurred, in spite of a 20% metabolism and an unchanged AβPP expression. The increased intracellular Aβ reactivity largely colocalized with a marker of ER. Inhibition of caspases blocked the cleavage at the C-terminus ofβPP, but only partially rescued Aβ overproduction caused by staurosporine treatment. Our findings…suggest that PCD fosters the physiological pathways of Aβ production characteristic of neuronal cells, and they confirm the theory that unbalance of PCD is a central event in AD pathogenesis. Moreover, our data indicate that still unidentified cellular mechanisms, other than caspases activation, are responsible of the specific alteration of AβPP processing during PCD.
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