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The intracellular domain of the Alzheimer's amyloid precursor protein (AICD) has been described as an important player in the transactivation of specific genes. It results from proteolytic processing of the Alzheimer's amyloid precursor protein (APP), as does the neurotoxic Abeta peptide. Although normally produced in cells, Abeta is typically considered to be a neurotoxic peptide, causing devastating effects. By exposing primary neuronal cultures to relatively low Abeta concentrations, this peptide was shown to affect APP processing. Our findings indicate that APP C-terminal fragments are increased with concomitant reduction in the expression levels of APP itself. AICD nuclear immunoreactivity detected under control conditions was dramatically reduced in response to Abeta exposure. Additionally, intracellular protein levels of Fe65 and GSK3 were also decreased in response to Abeta. APP nuclear signaling is altered by Abeta, affecting not only AICD production but also its nuclear translocation and complex formation with Fe65. In effect, Abeta can trigger a physiological negative feedback mechanism that modulates its own production.

Alzheimer beta-amyloid precursor protein can be phosphorylated on residues Thr654, Ser655 and Thr668 on its cytoplasmic domain. Proteolytic cleavage of the amyloid precursor protein and release of the amyloid precursor protein ectodomain into the medium of cultured cells can be activated by phorbol esters which stimulate protein kinase C. In the present study, using mutated amyloid precursor protein, we show that phosphorylation of cytoplasmic residues is not required for the phorbol ester-activated cleavage and release of the amyloid precursor protein ectodomain. Remarkably, deletion of the entire amyloid precursor protein cytoplasmic tail had no effect on the phorbol ester-activated cleavage/release. The results indicate that activation of amyloid precursor protein cleavage/release by protein kinase C involves phosphorylation of some component of the processing pathway, instead of or in addition to the cytoplasmic tail of the amyloid precursor protein.

Characteristically identified as the main component of senile plaques present in patients suffering from Alzheimer's disease, Aβ has been detected in human testis and reproductive fluids, but its effect on spermatozoa has not been addressed. The present study evaluated whether the most toxic and aggregant amyloid precursor protein (APP)-proteolytic product, amyloid-β (Aβ), was capable of affecting sperm functionality. Normozoospermic samples were either exposed to different Aβ doses or to the untreated and scrambled controls for a maximum of 48 h at 37 °C and 5%CO, and motility, viability and mitochondrial status were evaluated. Additionally, tyrosine phosphorylation was analyzed by immunocytochemistry and acrosomal integrity through PSA-FITC. A shorter treatment period was used to monitor prompt Ca responses. Aβ peptide decreased motility before inducing mitochondrial impairment ( p < 0.05; n = 6). Both outcomes became more pronounced with time, reaching their maximal decrease at 48 h, where even 1 μM produced undesirable effects ( p < 0.05; n = 6). Aβ peptide also decreased cell survival ( p < 0.05; n = 6). Furthermore, although no effects on tyrosine phosphorylation were observed ( p > 0.05; n = 6), reduced acrosomal integrity was detected ( p < 0.05; n = 7), which was not correlated with viability loss ( p > 0.05). In parallel, all Aβ concentrations elicited a [Ca] rise but a significant difference was only observed at 20 μM ( p < 0.05; n = 7) and a tendency was obtained with 10 μM ( p = 0.053; n = 7). In conclusion, Aβ peptide oligomers impair sperm function in vitro, although further studies are required to determine the clinical relevance of these findings. [ABSTRACT FROM AUTHOR]