Neurovascular dysfunction and vascular amyloid accumulation as early events in Alzheimer's disease

Apátiga-Pérez, Ricardo; Soto-Rojas, Luis O.; Campa-Córdoba, B. Berenice; Luna-Viramontes, Nabil Itzi; Cuevas, Elvis; Villanueva-Fierro, Ignacio; Ontiveros-Torres, Miguel Ángel; Bravo-Muñoz, Marely; Flores-Rodríguez, Paola; Garcés‐Ramírez, Linda; Cruz, Fidel de la; Montiel-Sosa, José Francisco; Pacheco-Herrero, Mar; Luna-Muñoz, José

doi:10.1007/s11011-021-00814-4

Cited by 57 publications

(46 citation statements)

References 96 publications

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“…Transcranial direct current stimulation (tDCS) decreased Aβ levels in AD mice, prompting us to further explore the mechanism by which tDCS affects Aβ production. The enzymes α-, β- and γ-secretase cleave APP to produce Aβ peptides ( Apatiga-Perez et al, 2021 ). Thus, we used ELISA to measure the concentrations of APP, ADAM10 and BACE1 in the hippocampus and frontal cortex in mice from each group ( Figure 2 ).…”

Section: Resultsmentioning

confidence: 99%

Transcranial Direct Current Stimulation Alleviates Neurovascular Unit Dysfunction in Mice With Preclinical Alzheimer’s Disease

Luo

Yang

Yan

et al. 2022

Front. Aging Neurosci.

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Neurons, glial cells and blood vessels are collectively referred to as the neurovascular unit (NVU). In the Alzheimer’s disease (AD) brain, the main components of the NVU undergo pathological changes. Transcranial direct current stimulation (tDCS) can protect neurons, induce changes in glial cells, regulate cerebral blood flow, and exert long-term neuroprotection. However, the mechanism by which tDCS improves NVU function is unclear. In this study, we explored the effect of tDCS on the NVU in mice with preclinical AD and the related mechanisms. 10 sessions of tDCS were given to six-month-old male APP/PS1 mice in the preclinical stage. The model group, sham stimulation group, and control group were made up of APP/PS1 mice and C57 mice of the same age. All mice were histologically evaluated two months after receiving tDCS. Protein content was measured using Western blotting and an enzyme-linked immunosorbent assay (ELISA). The link between glial cells and blood vessels was studied using immunofluorescence staining and lectin staining. The results showed that tDCS affected the metabolism of Aβ; the levels of Aβ, amyloid precursor protein (APP) and BACE1 were significantly reduced, and the levels of ADAM10 were significantly increased in the frontal cortex and hippocampus in the stimulation group. In the stimulation group, tDCS reduced the protein levels of Iba1 and GFAP and increased the protein levels of NeuN, LRP1 and PDGRFβ. This suggests that tDCS can improve NVU function in APP/PS1 mice in the preclinical stage. Increased blood vessel density and blood vessel length, decreased IgG extravasation, and increased the protein levels of occludin and coverage of astrocyte foot processes with blood vessels suggested that tDCS had a protective effect on the blood-brain barrier. Furthermore, the increased numbers of Vimentin, S100 expression and blood vessels (lectin-positive) around Aβ indicated that the effect of tDCS was mediated by astrocytes and blood vessels. There was no significant difference in these parameters between the model group and the sham stimulation group. In conclusion, our results show that tDCS can improve NVU function in APP/PS1 mice in the preclinical stage, providing further support for the use of tDCS as a treatment for AD.

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Section: Resultsmentioning

confidence: 99%

Transcranial Direct Current Stimulation Alleviates Neurovascular Unit Dysfunction in Mice With Preclinical Alzheimer’s Disease

Luo

Yang

Yan

et al. 2022

Front. Aging Neurosci.

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“…(See below section “Two-hit vascular hypothesis” for more information.) Several studies support the early appearance of vascular alterations in AD ( Sweeney et al, 2018 ; Apátiga-Pérez et al, 2021 ; Hussain et al, 2021 ; Kurz et al, 2021 ). In this scenario, endothelial progenitor cells (EPCs) appear as a possible therapeutic target by considering their involvement in the maintenance of vasculature.…”

Section: Introductionmentioning

confidence: 91%

Endothelial Progenitor Cells and Vascular Alterations in Alzheimer’s Disease

Custodia

Ouro

Romaus-Sanjurjo

et al. 2022

Front. Aging Neurosci.

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Alzheimer’s disease (AD) is a neurodegenerative disease representing the most common type of dementia worldwide. The early diagnosis of AD is very difficult to achieve due to its complexity and the practically unknown etiology. Therefore, this is one of the greatest challenges in the field in order to develop an accurate therapy. Within the different etiological hypotheses proposed for AD, we will focus on the two-hit vascular hypothesis and vascular alterations occurring in the disease. According to this hypothesis, the accumulation of β-amyloid protein in the brain starts as a consequence of damage in the cerebral vasculature. Given that there are several vascular and angiogenic alterations in AD, and that endothelial progenitor cells (EPCs) play a key role in endothelial repair processes, the study of EPCs in AD may be relevant to the disease etiology and perhaps a biomarker and/or therapeutic target. This review focuses on the involvement of endothelial dysfunction in the onset and progression of AD with special emphasis on EPCs as a biomarker and potential therapeutic target.

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“…However, additional studies are necessary to better dissect the pathogenic cascade leading to the onset of AD and to determine whether and to what measure BBB dysfunction acts as a causative factor or a derived effect that further contributes to the progressive worsening of the disease. For more detailed and extensive information on the subject, we refer the readers to recently published literature [205,206].…”

Section: Alzheimer's Disease (Ad)mentioning

confidence: 99%

Blood-Brain Barrier Dysfunction in CNS Disorders and Putative Therapeutic Targets: An Overview

2021

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The blood-brain barrier (BBB) is a fundamental component of the central nervous system (CNS). Its functional and structural integrity is vital to maintain the homeostasis of the brain microenvironment by controlling the passage of substances and regulating the trafficking of immune cells between the blood and the brain. The BBB is primarily composed of highly specialized microvascular endothelial cells. These cells’ special features and physiological properties are acquired and maintained through the concerted effort of hemodynamic and cellular cues from the surrounding environment. This complex multicellular system, comprising endothelial cells, astrocytes, pericytes, and neurons, is known as the neurovascular unit (NVU). The BBB strictly controls the transport of nutrients and metabolites into brain parenchyma through a tightly regulated transport system while limiting the access of potentially harmful substances via efflux transcytosis and metabolic mechanisms. Not surprisingly, a disruption of the BBB has been associated with the onset and/or progression of major neurological disorders. Although the association between disease and BBB disruption is clear, its nature is not always evident, specifically with regard to whether an impaired BBB function results from the pathological condition or whether the BBB damage is the primary pathogenic factor prodromal to the onset of the disease. In either case, repairing the barrier could be a viable option for treating and/or reducing the effects of CNS disorders. In this review, we describe the fundamental structure and function of the BBB in both healthy and altered/diseased conditions. Additionally, we provide an overview of the potential therapeutic targets that could be leveraged to restore the integrity of the BBB concomitant to the treatment of these brain disorders.

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Neurovascular dysfunction and vascular amyloid accumulation as early events in Alzheimer's disease

Cited by 57 publications

References 96 publications

Transcranial Direct Current Stimulation Alleviates Neurovascular Unit Dysfunction in Mice With Preclinical Alzheimer’s Disease

Transcranial Direct Current Stimulation Alleviates Neurovascular Unit Dysfunction in Mice With Preclinical Alzheimer’s Disease

Endothelial Progenitor Cells and Vascular Alterations in Alzheimer’s Disease

Blood-Brain Barrier Dysfunction in CNS Disorders and Putative Therapeutic Targets: An Overview

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