Chronic Hypertension Leads to Neurodegeneration in the TgSwDI Mouse Model of Alzheimer’s Disease

Kruyer, Anna; Soplop, Nadine; Strickland, Sidney; Norris, Erin H.

doi:10.1161/hypertensionaha.115.05524

Cited by 87 publications

(55 citation statements)

References 60 publications

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“…Hypertension accelerated cognitive deficits in the Barnes maze test, microvascular deposition of Aβ, vascular inflammation, BBB leakage, and pericyte loss; in addition, hypertension induced hippocampal neurodegeneration at an early age in this mouse line, establishing this as a useful research model of AD with mixed vascular and amyloid pathologies (Kruyer et al, 2015). …”

Section: Introductionmentioning

confidence: 94%

Rodent Models of Vascular Cognitive Impairment

Yang

Kimura-Ohba

Thompson

et al. 2016

Transl. Stroke Res.

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Vascular cognitive impairment dementia (VCID), which is an increasingly important cause of dementia in the elderly, lacks effective treatments. Many different types of vascular disease are included under the diagnosis of VCID, including large vessel disease with multiple strokes, and small vessel disease with lacunar infarcts and white matter disease. Animal models have been developed to study the multiple forms of VCID. Because of its progressive course, small vessel disease (SVD) is thought to be the optimal form of VCID for treatment. One theory is that the pathophysiology involves hypoxic hypoperfusion resulting in injury to the white matter and neuronal death. Bilateral occlusion of the common carotid arteries (BCAO) in a normotensive rat, which reduces cerebral blood flow, induces hypoxia with white matter damage; this model has been used to test drugs to block the injury. Another model is the spontaneously hypertensive/stroke prone rat (SHR/SP). Hypertension leads to small vessel disease resulting in progressive damage to the white matter, cortex and hippocampus. Bilateral carotid artery stenosis (BCAS) with coils or ameroid constrictors produces a slower development of changes than BCAO, avoiding the acute ischemia. A few studies have been done with the two-clip, two-vessel occlusion renal model for induction of hypertension. There are benefits and drawbacks to each of these models with the model selected depending on the type of vascular damage that is to be studied. This review describes the most commonly used models, and the drugs that have been used to reduce the damage.

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Section: Introductionmentioning

confidence: 94%

Rodent Models of Vascular Cognitive Impairment

Yang

Kimura-Ohba

Thompson

et al. 2016

Transl. Stroke Res.

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“…Compelling evidence suggests that chronic hypertension fuels atherosclerosis in cerebral arteries, and also increases the risk of microvascular damage, white matter lesions, ischemic stroke and intracranial hemorrhage in the presence of CAA [106–108]. In animal models, hypertension caused BBB impairment, induced brain Aβ accumulation, enhanced Aβ-induced neurovascular dysfunction and neurodegeneration [109–112]. Circulating plasma levels of markers of endothelial activation including soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular cell adhesion molecule-1 (sVCAM-1) and endothelin-1 (ET-1), an endothelial cell-derived potent vasoconstrictor, are increased in hypertensive subjects suggesting vascular injury [107,113,114].…”

Section: Vascular Risk Factors Lifestyle and Environmentmentioning

confidence: 99%

Neurovascular dysfunction and neurodegeneration in dementia and Alzheimer's disease

Nelson

Sweeney

Sagare

et al. 2016

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

436

423

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Vascular insults can initiate a cascade of molecular events leading to neurodegeneration, cognitive impairment and dementia. Here, we review the cellular and molecular mechanisms in cerebral blood vessels and the pathophysiological events leading to cerebral blood flow dysregulation and disruption of the neurovascular unit and the blood-brain barrier, which all may contribute to the onset and progression of dementia and Alzheimer’s disease (AD). Particularly, we examine the link between neurovascular dysfunction and neurodegeneration including the effects of AD genetic risk factors on cerebrovascular functions and clearance of Alzheimer’s amyloid-β peptide toxin, and the impact of vascular risk factors, environment and lifestyle on cerebral blood vessels, which in turn may affect synaptic, neuronal and cognitive functions. Finally, we examine potential experimental treatments for dementia and AD based on the neurovascular model, and discuss some critical questions to be addressed by future studies.

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“…Blood pressure was measured at the end of ASO treatment using tailcuff plethysmography (Kent Scientific) during light cycle. (Kruyer, Soplop, Strickland, & Norris, 2015). An average of three readings was obtained for each animal during measurement.…”

Section: Blood Pressurementioning

confidence: 99%

Knockdown of circulating C1 inhibitor induces neurovascular impairment, glial cell activation, neuroinflammation, and behavioral deficits

Farfara

Feierman

Richards

et al. 2019

Glia

Self Cite

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The cross‐talk between blood proteins, immune cells, and brain function involves complex mechanisms. Plasma protein C1 inhibitor (C1INH) is an inhibitor of vascular inflammation that is induced by activation of the kallikrein‐kinin system (KKS) and the complement system. Knockout of C1INH was previously correlated with peripheral vascular permeability via the bradykinin pathway, yet there was no evidence of its correlation with blood–brain barrier (BBB) integrity and brain function. In order to understand the effect of plasma C1INH on brain pathology via the vascular system, we knocked down circulating C1INH in wild‐type (WT) mice using an antisense oligonucleotide (ASO), without affecting C1INH expression in peripheral immune cells or the brain, and examined brain pathology. Long‐term elimination of endogenous C1INH in the plasma induced the activation of the KKS and peritoneal macrophages but did not activate the complement system. Bradykinin pathway proteins were elevated in the periphery and the brain, resulting in hypotension. BBB permeability, extravasation of plasma proteins into the brain parenchyma, activation of glial cells, and elevation of pro‐inflammatory response mediators were detected. Furthermore, infiltrating innate immune cells were observed entering the brain through the lateral ventricle walls and the neurovascular unit. Mice showed normal locomotion function, yet cognition was impaired and depressive‐like behavior was evident. In conclusion, our results highlight the important role of regulated plasma C1INH as it acts as a gatekeeper to the brain via the neurovascular system. Thus, manipulation of C1INH in neurovascular disorders might be therapeutically beneficial.

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Chronic Hypertension Leads to Neurodegeneration in the TgSwDI Mouse Model of Alzheimer’s Disease

Cited by 87 publications

References 60 publications

Rodent Models of Vascular Cognitive Impairment

Rodent Models of Vascular Cognitive Impairment

Neurovascular dysfunction and neurodegeneration in dementia and Alzheimer's disease

Knockdown of circulating C1 inhibitor induces neurovascular impairment, glial cell activation, neuroinflammation, and behavioral deficits

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