NO synthase 2 (NOS2) deletion promotes multiple pathologies in a mouse model of Alzheimer's disease.
Alzheimer's disease is characterized by two primary pathological features: amyloid plaques and neurofibrillary tangles. The interconnection between amyloid and tau aggregates is of intense interest, but mouse models have yet to reveal a direct interrelationship. We now show that NO may be a key factor that connects amyloid and tau pathologies. Genetic removal of NO synthase 2 in mice expressing mutated amyloid precursor protein results in pathological hyperphosphorylation of mouse tau, its redistribution to the somatodendritic compartment in cortical and hippocampal neurons, and aggregate formation. Lack of NO synthase 2 in the amyloid precursor protein Swedish mutant mouse increased insoluble beta-amyloid peptide levels, neuronal degeneration, caspase-3 activation, and tau cleavage, suggesting that NO acts at a junction point between beta-amyloid peptides, caspase activation, and tau aggregation.
Colton
C A
CA
Division of Neurology, and Department of Immunology, Duke University Medical Center, Durham, NC 27710, USA. glia01@aol.com
Vitek
M P
MP
Wink
D A
DA
Xu
Q
Q
Cantillana
V
V
Previti
M L
ML
Van Nostrand
W E
WE
Weinberg
J B
JB
Weinberg
B
B
Dawson
H
H
D000544:Alzheimer Disease / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D004195:Disease Models, Animal; D017353:Gene Deletion; D051379:Mice; D018345:Mice, Knockout; D052247:Nitric Oxide Synthase Type II / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D016875:tau Proteins / Q000378:metabolism
D016229:Amyloid beta-Peptides; D016875:tau Proteins; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases