Neurovascular uncoupling in the triple transgenic model of Alzheimer's disease: Impaired cerebral blood flow response to neuronal-derived nitric oxide signaling.
Nitric oxide (NO)-dependent pathways and cerebrovascular dysfunction have been shown to contribute to the cognitive decline and neurodegeneration observed in Alzheimer's disease (AD) but whether they represent initial factors or later changes of the disease is still a matter of debate. In this work, we aimed at investigating whether and to what extent neuronal-derived NO signaling and related neurovascular coupling are impaired along aging in the hippocampus of the triple transgenic mouse model of Alzheimer's Disease (3xTg-AD). We performed a longitudinal study combining behavior studies, in vivo simultaneous measurements of NO concentration gradients and cerebral blood flow (CBF), along with detection of NO synthase (NOS) and markers of nitroxidative stress. Our results revealed an impairment in the neurovascular coupling along aging in the 3xTg-AD mice which preceded obvious cognitive decline. This impairment was characterized by diminished CBF changes in response to normal or even increased NO signals and associated with markers of nitroxidative stress. The results suggest that impairment in neurovascular coupling is primarily due to cerebrovascular dysfunction, rather than due to dysfunctional NO signaling from neurons to blood vessels. Overall, this work supports cerebrovascular dysfunction as a fundamental underlying process in AD pathology.
Center for Neuroscience and Cell Biology, University of Coimbra, Portugal. Electronic address: cflmarques@uc.pt.
Cátia F
CF
Lourenço
Center for Neuroscience and Cell Biology, University of Coimbra, Portugal.
Ana
A
Ledo
Center for Neuroscience and Cell Biology, University of Coimbra, Portugal; Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal.
Rui M
RM
Barbosa
Center for Neuroscience and Cell Biology, University of Coimbra, Portugal; Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal. Electronic address: laranjin@ci.uc.pt.
João
J
Laranjinha
D000244:Adenosine Diphosphate / Q000494:pharmacology; D000367:Age Factors; D000544:Alzheimer Disease / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D001835:Body Weight / Q000235:genetics / Q000502:physiology; D002560:Cerebrovascular Circulation / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D004195:Disease Models, Animal; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018698:Glutamic Acid / Q000494:pharmacology; D006801:Humans; D018782:Maze Learning / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D000069336:Neurovascular Coupling / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D009569:Nitric Oxide / Q000378:metabolism*; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism; D053764:Presenilin-1 / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D016875:tau Proteins / Q000235:genetics
D016564:Amyloid beta-Protein Precursor; D018690:Excitatory Amino Acid Agonists; C508853:PSEN1 protein, human; D053764:Presenilin-1; D016875:tau Proteins; D009569:Nitric Oxide; D018698:Glutamic Acid; D000244:Adenosine Diphosphate; D052248:Nitric Oxide Synthase Type I
3xTgAD mice; Alzheimer's disease; Cerebrovascular dysfunction; Hippocampus; Neurovascular coupling; Nitric oxide; Oxidative stress