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P3–244: The impact of LRP on APP metabolism along the secretory pathway
Author(s) -
Waldron Elaine A.,
Heilig Catherine,
Schweitzer Andrea,
Pietrzik Claus U.
Publication year - 2006
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2006.05.1513
Subject(s) - internalization , secretion , amyloid precursor protein , microbiology and biotechnology , immunoprecipitation , intracellular , blot , chemistry , biotinylation , cell , biology , biochemistry , alzheimer's disease , medicine , disease , gene
(PrPc), the two culprit membrane proteins in AD and prion-associated pathologies respectively, are similarly processed in the middle of their toxic sequence. Indeed, the so-called a-secretase cleavage precludes the integrity of the amyloid-b peptide (Ab) and the 106-126 sequence of PrPc. The recent identification of two members of the disintegrin family of proteases, ADAM10 and ADAM17, as constitutive and PKC-regulated a-secretase activities cleaving both bAPP and PrPc further reinforced the link between Alzheimer’s and prion diseases. We showed very recently that a third ADAM protease, namely ADAM9, also participates in the processing of bAPP and PrPc. However, ADAM9 does not directly cleave bAPP and PrPc but rather acts through the modulation of ADAM10 likely by contributing to its shedding. A well-documented aspect of the regulation of the a-secretase pathway concerns its activation by protein kinase C agonists. Interestingly, it has been suggested that some but not all PKC isozymes contribute the cleavage of bAPP at the a-site. We established that the conventional a and b as well as the novel e isoforms are involved in the regulated cleavage of both bAPP and PrPc while a fourth member, the novel PKCd, seems to only modulate PrPc processing. This tends to prove that the molecular mechanisms governing the PKC-mediated cleavage of both proteins, although very similar, display subtle differences. Finally, in the search for the receptors and ligands acting upstream of PKC activation which ultimately leads to the up-regulation of PrPc processing, we demonstrated that the M1/M3 subclass of muscarinic receptors which are coupled to PLC/PKC, but not the M2/M4 (linked to adenylate cyclase/ PKA) was a key component of the PKC-mediated PrPc processing. Altogether, these data suggest that any medication aiming at increasing the a-secretase cleavage could ameliorate two apparently unrelated groups of diseases.