Evidence that the Amyloid beta Precursor Protein-intracellular domain lowers the stress threshold of neurons and has a "regulated" transcriptional role

Abstract

BackgroundRegulated intramembrane proteolysis of the β-amyloid precursor protein by the γ-secretase yields two peptides. One, amyloid-β, is the major component of the amyloid plaques found in Alzheimer's disease patients. The other, APP IntraCellular Domain, has been involved in regulation of apoptosis, calcium flux and gene transcription. To date, a few potential target genes transcriptionally controlled by AID, alone or complexed with Fe65/Tip60, have been described. Although the reports are controversial: these include KAI1, Neprilysin, p53, EGFR, LRP and APP itself. Furthermore, p53 has been implicated in AID mediated susceptibility to apoptosis. To extend these findings, and assess their in vivo relevance, we have analyzed the expression of the putative target genes and of the total brain basal transriptoma in transgenic mice expressing AID in the forebrain. Also, we have studied the susceptibility of primary neurons from such mice to stress and pro-apoptotic agents.ResultsWe found that AID-target genes and the mouse brain basal transcriptoma are not influenced by transgenic expression of AID alone, in the absence of Fe65 over-expression. Also, experiments conducted on primary neurons from AID transgenic mice, suggest a role for AID in sensitizing these cells to toxic stimuli. Overall, these findings hint that a role for AID, in regulating gene transcription, could be induced by yet undefined, and possibly stressful, stimuli in vivo.ConclusionOverall, these data suggest that the release of the APP intracellular domain may modulate the sensitivity of neuronal cells to toxic stimuli, and that a transcriptional role of AID could be inscribed in signaling pathways thatare not activated in basal conditions.

Mutant Presenilin 1 Increases the Expression and Activity of BACE1

“…A further confirmation that AICD does not have a role in BACE1 transcription control resulted from the analysis of brain tissue of transgenic mice (tg) overexpressing AICD. Mice were generated on an FVB background, with the transgene placed under the control of calmodulin kinase II-␣ promoter (driving the expression in the forebrain) and have been recently described and characterized (44). Seven tg and 7 littermates carrying the AICD 50, 57, or 59 transgene were analyzed at 4 weeks of age for forebrain BACE1 mRNA expression; we did not detect any difference between the tg and littermate mice (Fig.…”

Physiological Functions of APP Family Proteins

“…Instead, the investigators provided an alternative pathway involving Tip60 phosphorylation; (3) a later report documented that the proposed signaling activity is, in fact, executed by Fe65 independently of APP (Yang et al 2006). Last, the link of Fe65 to chromatin remodeling instead of transcription suggests that APP may not act on specific genes, but rather modulates the overall transcriptional state of a cell (Giliberto et al 2008).…”

“…Accordingly, effort has been taken to identify the downstream targets, which reportedly include KAI (Baek et al 2002) ), p53 (Checler et al 2007), LRP ), APP itself (von Rotz et al 2004), and genes involved in calcium regulation (Leissring et al 2002) and cytoskeletal dynamics ). However, the validity of these proposed targets have been either questioned or disputed (Hebert et al 2006;Yang et al 2006;Chen and Selkoe 2007;Repetto et al 2007;Giliberto et al 2008;Tamboli et al 2008;Waldron et al 2008;Aydin et al 2011). Overall, as attractive as the APP/AICD signaling model is, and regardless of the intense effort devoted to this topic in the past 10 years, neither the molecular pathways nor the downstream targets have been unambiguously established.…”

“…In support of a functional role of this pathway, neuronal cultures generated from AICD transgenic mice are found to be more susceptible to toxic stimuli (Giliberto et al 2008), and impaired synaptic plasticity and learning and memory seen in APP transgenic models were corrected in a mouse line in which the caspase site was mutated despite the presence of abundant amyloid pathology (Galvan et al 2006). However, a more recent publication challenged these findings (Harris et al 2010), and the physiological significance of this cleavage event thus requires further investigation.…”

BRI3 Inhibits Amyloid Precursor Protein Processing in a Mechanistically Distinct Manner from Its Homologue Dementia Gene BRI2

“…The ␥-cleavage releases two peptides: A␤ peptide, consisting of 2 major species of 40 and 42 amino acids (A␤40 and A␤42, respectively) and an intracellular product APP intracellular domain (AID)/AICD. Several findings point to the short AID/AICD as a biologically active intracellular peptide, which may modulate cell death, Notch signaling, gene transcription, and Ca 2ϩ homeostasis (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19). In an alternative pathway, APP is processed by ␣-secretase within the A␤ sequence, leading to the production of the soluble sAPP␣ ectodomain and a membrane-bound C-terminal fragment of 83 amino acids (C83).…”