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1.
Hypertension ; 74(4): 1041-1051, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31476904

RESUMO

Transient hypertension is a risk factor for Alzheimer disease (AD), but the effects of this interaction on brain vasculature are understudied. Addressing vascular pathology is a promising avenue to potentiate the efficacy of treatments for AD. We used arterial spin labeling magnetic resonance imaging to longitudinally assess brain vascular function and immunohistopathology to examine cerebrovascular remodeling and amyloid load. Hypertension was induced for 1 month by administration of l-NG-nitroarginine-methyl-ester in TgF344-AD rats at the prodromal stage. Following hypertension, nontransgenic rats showed transient cerebrovascular changes, whereas TgF344-AD animals exhibited sustained alterations in cerebrovascular function. Human umbilical cord perivascular cells in combination with scyllo-inositol, an inhibitor of Aß oligomerization, resulted in normalization of hippocampal vascular function and remodeling, in contrast to either treatment alone. Prodromal stage hypertension exacerbates latter AD pathology, and the combination of human umbilical cord perivascular cells with amyloid clearance promotes cerebrovascular functional recovery.


Assuntos
Doença de Alzheimer/fisiopatologia , Hipertensão/fisiopatologia , Doença de Alzheimer/etiologia , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Encéfalo/fisiopatologia , Modelos Animais de Doenças , Hemodinâmica/fisiologia , Hipertensão/complicações , Hipertensão/terapia , Imagem por Ressonância Magnética , Ratos , Marcadores de Spin
2.
J Neurochem ; 144(5): 669-679, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-28777881

RESUMO

Alzheimer's disease (AD) is pathologically characterized by amyloid-ß peptide (Aß) accumulation, neurofibrillary tangle formation, and neurodegeneration. Preclinical studies on neuronal impairments associated with progressive amyloidosis have demonstrated some Aß-dependent neuronal dysfunction including modulation of gamma-aminobutyric acid-ergic signaling. The present work focuses on the early stage of disease progression and uses TgF344-AD rats that recapitulate a broad repertoire of AD-like pathologies to investigate the neuronal network functioning using simultaneous intracranial recordings from the hippocampus (HPC) and the medial prefrontal cortex (mPFC), followed by pathological analyses of gamma-aminobutyric acid (GABAA ) receptor subunits α1, α5, and δ, and glutamic acid decarboxylases (GAD65 and GAD67). Concomitant to amyloid deposition and tau hyperphosphorylation, low-gamma band power was strongly attenuated in the HPC and mPFC of TgF344-AD rats in comparison to those in non-transgenic littermates. In addition, the phase-amplitude coupling of the neuronal networks in both areas was impaired, evidenced by decreased modulation of theta band phase on gamma band amplitude in TgF344-AD animals. Finally, the gamma coherence between HPC and mPFC was attenuated as well. These results demonstrate significant neuronal network dysfunction at an early stage of AD-like pathology. This network dysfunction precedes the onset of cognitive deficits and is likely driven by Aß and tau pathologies. This article is part of the Special Issue "Vascular Dementia".


Assuntos
Doença de Alzheimer/fisiopatologia , Hipocampo/fisiopatologia , Neurônios/fisiologia , Córtex Pré-Frontal/fisiopatologia , Doença de Alzheimer/patologia , Animais , Ondas Encefálicas , Modelos Animais de Doenças , Feminino , Glutamato Descarboxilase/metabolismo , Hipocampo/metabolismo , Hipocampo/patologia , Masculino , Vias Neurais/fisiopatologia , Placa Amiloide/metabolismo , Córtex Pré-Frontal/patologia , Ratos Endogâmicos F344 , Ratos Transgênicos , Receptores de GABA-A/metabolismo
3.
Sci Rep ; 7: 46427, 2017 04 12.
Artigo em Inglês | MEDLINE | ID: mdl-28401931

RESUMO

Alzheimer's disease (AD), pathologically characterized by amyloid-ß peptide (Aß) accumulation, neurofibrillary tangle formation, and neurodegeneration, is thought to involve early-onset neurovascular abnormalities. Hitherto studies on AD-associated neurovascular injury have used animal models that exhibit only a subset of AD-like pathologies and demonstrated some Aß-dependent vascular dysfunction and destabilization of neuronal network. The present work focuses on the early stage of disease progression and uses TgF344-AD rats that recapitulate a broader repertoire of AD-like pathologies to investigate the cerebrovascular and neuronal network functioning using in situ two-photon fluorescence microscopy and laminar array recordings of local field potentials, followed by pathological analyses of vascular wall morphology, tau hyperphosphorylation, and amyloid plaques. Concomitant to widespread amyloid deposition and tau hyperphosphorylation, cerebrovascular reactivity was strongly attenuated in cortical penetrating arterioles and venules of TgF344-AD rats in comparison to those in non-transgenic littermates. Blood flow elevation to hypercapnia was abolished in TgF344-AD rats. Concomitantly, the phase-amplitude coupling of the neuronal network was impaired, evidenced by decreased modulation of theta band phase on gamma band amplitude. These results demonstrate significant neurovascular network dysfunction at an early stage of AD-like pathology. Our study identifies early markers of pathology progression and call for development of combinatorial treatment plans.


Assuntos
Doença de Alzheimer/fisiopatologia , Encéfalo/fisiopatologia , Circulação Cerebrovascular/fisiologia , Rede Nervosa/fisiopatologia , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Encéfalo/metabolismo , Modelos Animais de Doenças , Feminino , Masculino , Rede Nervosa/metabolismo , Neurônios/metabolismo , Neurônios/fisiologia , Fosforilação , Ratos , Ratos Transgênicos , Proteínas tau/metabolismo
4.
J Cereb Blood Flow Metab ; 37(3): 1046-1059, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-27683451

RESUMO

Aerobic activity has been shown highly beneficial to brain health, yet much uncertainty still surrounds the effects of exercise on the functioning of cerebral microvasculature. This study used two-photon fluorescence microscopy to examine cerebral hemodynamic alterations as well as accompanying geometric changes in the cortical microvascular network following five weeks of voluntary exercise in transgenic mice endogenously expressing tdTomato in vascular endothelial cells to allow visualization of microvessels irrespective of their perfusion levels. We found a diminished microvascular response to a hypercapnic challenge (10% FiCO2) in running mice when compared to that in nonrunning controls despite commensurate increases in transcutaneous CO2 tension. The flow increase to hypercapnia in runners was 70% lower than that in nonrunners (p = 0.0070) and the runners' arteriolar red blood cell speed changed by only half the amount seen in nonrunners (p = 0.0085). No changes were seen in resting hemodynamics or in the systemic physiological parameters measured. Although a few unperfused new vessels were observed on visual inspection, running did not produce significant morphological differences in the microvascular morphometric parameters, quantified following semiautomated tracking of the microvascular networks. We propose that voluntary running led to increased cortical microvascular efficiency and desensitization to CO2 elevation.


Assuntos
Córtex Cerebral/irrigação sanguínea , Condicionamento Físico Animal/fisiologia , Animais , Circulação Cerebrovascular , Hemodinâmica , Hipercapnia/fisiopatologia , Camundongos , Camundongos Transgênicos , Microscopia de Fluorescência/métodos , Corrida/fisiologia
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