Regulation of proteolytic processing of the amyloid beta-protein precursor of Alzheimer's disease in transfected cell lines and in brain slices.
beta A4 is the principal component of Alzheimer's disease brain amyloid. It is derived from proteolytic processing of amyloid beta-protein precursors (APP), a family of transmembrane glycoproteins. Secretion of APPs, a secreted proteolytic derivative that is cleaved within the beta A4 domain of APP, is increased many-fold by the activation of cell-surface receptors, like the muscarinic m1 and m3 receptor subtypes, which are coupled to protein kinase C. Concomitantly, their activation decreases the formation of both secreted soluble beta A4 and of endosomal-lysosomal C-terminal APP derivatives. These data suggest that muscarinic m1 and m3 receptors accelerate non-amyloidogenic APP processing and depress the formation of potentially amyloidogenic derivatives. Other receptors that stimulate APPs secretion include those for bradykinin, vasopressin, and interleukin-1 receptors. A similar control mechanism is present in rat brain tissue slices, in which the release of both APPs and endogenous neurotransmitters is increased by electrical depolarization. This increase is tetrodotoxin-sensitive and frequency-dependent, suggesting that APPs release may normally depend on neuronal activity. Taken together, our findings suggest that specific receptor agonists might be effective in reducing the formation of potentially amyloidogenic APP derivatives in vivo.
Nitsch
R M
RM
Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge.
Slack
B E
BE
Farber
S A
SA
Schulz
J G
JG
Deng
M
M
Kim
C
C
Borghesani
P R
PR
Korver
W
W
Wurtman
R J
RJ
Growdon
J H
JH
D000544:Alzheimer Disease / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism*; D002460:Cell Line; D006801:Humans; D066298:In Vitro Techniques; D011493:Protein Kinase C / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D051381:Rats; D018002:Receptors, Bradykinin / Q000378:metabolism; D017472:Receptors, Interleukin-1 / Q000378:metabolism; D011976:Receptors, Muscarinic / Q000378:metabolism; D017483:Receptors, Vasopressin / Q000378:metabolism; D014162:Transfection
D016564:Amyloid beta-Protein Precursor; D018002:Receptors, Bradykinin; D017472:Receptors, Interleukin-1; D011976:Receptors, Muscarinic; D017483:Receptors, Vasopressin; D011493:Protein Kinase C