beta-Amyloid precursor protein metabolism: focus on the functions and degradation of its intracellular domain.
Alzheimer's disease (AD) is a neurodegenerative disorder that represents the most common type of dementia in the elderly. One of the hallmarks of this disease is a progressive accumulation of amyloid fibrils in senile plaques (SPs), which are composed principally of amyloid-beta peptides (Abeta). The 4-kDa beta-amyloid peptides are produced from the beta-amyloid precursor protein (APP) through sequential processing by beta- and gamma-secretase enzymes in the amyloidogenic pathway. By an alternative non-amyloidogenic pathway, mediated by alpha- and gamma-secretases enzymes, APP is processed within the Abeta domain. Both processing pathways may result in the generation of a fragment called APP intracellular C-terminal domain (AICD) which is hypothesized to contribute to the pathophysiology of AD. Experimental evidence highlights that biological functions of AICD are mediated by interactions between its YENPTY motif and specific binding factors. We critically reviewed literature concerning physiological function of this proteolitic fragment, mainly focusing on their degradation by the two best characterized systems, proteasome and IDE (insulin degrading enzyme). Our work is aimed to analyse the functional role of AICD, integrating also the AICD degradation processes, to better define a potential role of AICD in signal transduction.
Buoso
Erica
E
Department of Experimental and Applied Pharmacology, Center of Excellence in Applied Biology, University of Pavia, Viale Taramelli 14, 27100 Pavia, Italy.
Lanni
Cristina
C
Schettini
Gennaro
G
Govoni
Stefano
S
Racchi
Marco
M
D000544:Alzheimer Disease / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D006801:Humans; D007339:Insulysin / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000235:genetics*; D017434:Protein Structure, Tertiary; D015398:Signal Transduction
D016564:Amyloid beta-Protein Precursor; D007339:Insulysin; D046988:Proteasome Endopeptidase Complex