Altered cell-matrix associated ADAM proteins in Alzheimer disease.
Alterations in cell-matrix 'contact' are often related to a disruption of cell cycle regulation and, as such, occur variously in neoplasia. Given the recent findings showing cell cycle alterations in Alzheimer disease, we undertook a study of ADAM-1 and 2 (A Disintegrin And Metalloprotease), developmentally-regulated, integrin-binding, membrane-bound metalloproteases. Our results show that whereas ADAM-1 and 2 are found in susceptible hippocampal neurons in Alzheimer disease, these proteins were not generally increased in similar neuronal populations in younger or age-matched controls except in association with age-related neurofibrillary alterations. This increase in both ADAM-1 and 2 in cases of Alzheimer disease was verified by immunoblot analysis (P < 0.05). An ADAM-induced loss of matrix integration would effectively "reset" the mitotic clock and thereby stimulate re-entry into the cell cycle in neurons in Alzheimer disease. Furthermore, given the importance of integrins in maintaining short-term memory, alterations in ADAM proteins or their proteolytic activity could also play a proximal role in the clinico-pathological manifestations of Alzheimer disease.
Gerst
J L
JL
Institute of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA.
Raina
A K
AK
Pirim
I
I
McShea
A
A
Harris
P L
PL
Siedlak
S L
SL
Takeda
A
A
Petersen
R B
RB
Smith
M A
MA
D051722:ADAM Proteins; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism*; D001921:Brain / Q000378:metabolism*; D005109:Extracellular Matrix / Q000378:metabolism*; D000072196:Fertilins; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D008562:Membrane Glycoproteins / Q000378:metabolism*; D008666:Metalloendopeptidases / Q000378:metabolism*; D008875:Middle Aged
D008562:Membrane Glycoproteins; D051722:ADAM Proteins; D000072196:Fertilins; D008666:Metalloendopeptidases