Capillary dysfunction is associated with symptom severity and neurodegeneration in Alzheimer's disease

Nielsen, Rune B.; Egefjord, Lærke; Angleys, Hugo; Mouridsen, Kim; Gejl, Michael; Møller, Arne; Brock, Birgitte; Brændgaard, Hans; Gottrup, Hanne; Rungby, Jørgen; Eskildsen, Simon Fristed; Østergaard, Leif

doi:10.1016/j.jalz.2017.02.007

Cited by 97 publications

(89 citation statements)

References 44 publications

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“…For instance, it has been hypothesized that capillary metabolism disturbance and hypoxia play important roles in the development of Alzheimer’s disease [66,67,68]. Microvascular dysfunction and chronic cerebral hypoperfusion are observed in metabolic syndrome [69].…”

Section: Discussionmentioning

confidence: 99%

AAV-Syn-BDNF-EGFP Virus Construct Exerts Neuroprotective Action on the Hippocampal Neural Network during Hypoxia In Vitro

Митрошина

Mishchenko

Usenko

et al. 2018

IJMS

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Brain-derived neurotrophic factor (BDNF) is one of the key signaling molecules that supports the viability of neural cells in various brain pathologies, and can be considered a potential therapeutic agent. However, several methodological difficulties, such as overcoming the blood–brain barrier and the short half-life period, challenge the potential use of BDNF in clinical practice. Gene therapy could overcome these limitations. Investigating the influence of viral vectors on the neural network level is of particular interest because viral overexpression affects different aspects of cell metabolism and interactions between neurons. The present work aimed to investigate the influence of the adeno-associated virus (AAV)-Syn-BDNF-EGFP virus construct on neural network activity parameters in an acute hypobaric hypoxia model in vitro. Materials and methods. An adeno-associated virus vector carrying the BDNF gene was constructed using the following plasmids: AAV-Syn-EGFP, pDP5, DJvector, and pHelper. The developed virus vector was then tested on primary hippocampal cultures obtained from C57BL/6 mouse embryos (E18). Acute hypobaric hypoxia was induced on day 21 in vitro. Spontaneous bioelectrical and calcium activity of neural networks in primary cultures and viability tests were analysed during normoxia and during the posthypoxic period. Results. BDNF overexpression by AAV-Syn-BDNF-EGFP does not affect cell viability or the main parameters of spontaneous bioelectrical activity in normoxia. Application of the developed virus construct partially eliminates the negative hypoxic consequences by preserving cell viability and maintaining spontaneous bioelectrical activity in the cultures. Moreover, the internal functional structure, including the activation pattern of network bursts, the number of hubs, and the number of connections within network elements, is also partially preserved. BDNF overexpression prevents a decrease in the number of cells exhibiting calcium activity and maintains the frequency of calcium oscillations. Conclusion. This study revealed the pronounced antihypoxic and neuroprotective effects of AAV-Syn-BDNF-EGFP virus transduction in an acute normobaric hypoxia model.

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Section: Discussionmentioning

confidence: 99%

AAV-Syn-BDNF-EGFP Virus Construct Exerts Neuroprotective Action on the Hippocampal Neural Network during Hypoxia In Vitro

Митрошина

Mishchenko

Usenko

et al. 2018

IJMS

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“…Moreover, a number of blood pressure parameters relevant to the brain have not been addressed systematically. Pulse pressure relates to arterial brain stiffness which in turn correlates with brain perfusion, which itself may be heterogenous requiring different blood pressure parameters. One of the strongest associations between hypertension and the brain relates to white matter changes (leukoaraiosis) that in turn represent harbingers of increased risk of stroke and dementia .…”

Section: Risk Factorsmentioning

confidence: 99%

Implementing the proclamation of stroke and potentially preventable dementias

Hachinski

Ganten

Lackland

et al. 2018

J of Clinical Hypertension

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Brain health plays a central role in well‐being and in the management of chronic diseases. Stroke and dementia pose the two greatest threats to brain health, but recent developments suggest the possibility that preventing stroke may also prevent some dementias: (a) A large population study showed a 32% decrease in the incidence of stroke and a concomitant 7% reduction in the incidence of dementia; (b) the treatment of atrial fibrillation resulted not only in stroke reduction, but also a 48% decrease in dementia; (c) the hypothesis‐free analyses have shown that the first phase of Alzheimer disease involves vascular dysregulation, opening the door to new therapeutic approaches; (d) cognitive impairment, often treatable and reversible, accompanies heart and kidney failure. These developments, combined with the knowledge that stroke, dementia, and heart disease share the same major treatable risk factors, particularly hypertension, offer an opportunity for their joint prevention. This aspiration is expressed by a Proclamation of the World Stroke Organization on Stroke and Potentially Preventable Dementias and endorsed by the World Heart Federation, the World Hypertension League, Alzheimer Disease International, and 18 other international, regional, and national organizations as a call for action.

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“…This therapeutic approach receives added impetus from continual findings of cerebrovascular pathology (Beishon et al 2017;Goldwaser et al 2016;Hishikawa et al 2016;Kapasi and Schneider 2016;Kelleher and Soiza 2013;Malojcic et al 2017;McAleese et al 2016;Muche et al 2017;Nelson et al 2016;Nielsen et al 2017;Noh et al 2016;Perrotta et al 2016;Raz et al 2016;Weekman et al 2016) and brain arterial aging (Calabrese et al 2016;Cooper and Mitchell 2016;Gutierrez et al 2016;Kelleher and Soiza 2013;Malojcic et al 2017;Nagata et al 2016;Raz et al 2016;Toth et al 2017) accompanying Alzheimer's disease. Similarly, there is an apparent endothelium-dysfunction involvement Bhat 2015;Carradori et al 2016;Chao et al 2016;Devraj et al 2016;Di Marco et al 2015;Festoff et al 2016;Gangoda et al 2016;Hishikawa et al 2016;Hostenbach et al 2016;Kahlil et al 2016;Kelleher and Soiza 2013;Koizumi at al.…”

Section: Targeted Delivery (Of Drugs Including Antibody Therapeutics)mentioning

confidence: 99%

Nanotherapy for Early Dementia: Targeting Senile Dementia

D'Arrigo¹

2017

Preprint

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Due to the complexity of Alzheimer's disease, multiple cellular types need to be targeted simultaneously in order for a given therapy to demonstrate any major effectiveness. Ultrasound-sensitive coated microbubbles (in a targeted lipid nanoemulsion) are available. Versatile small molecule drug(s) targeting multiple pathways of Alzheimer's disease pathogenesis are known. By incorporating such drug(s) into the targeted LCM/ND lipid nanoemulsion type, one obtains a multitasking combination therapeutic for translational medicine. This multitasking therapeutic targets cell-surface scavenger receptors (mainly SR-BI), making possible for various Alzheimer's-related cell types to be simultaneously searched out for localized drug treatment in vivo. Besides targeting cell-surface SR-BI, the proposed LCM/ND-nanoemulsion combination therapeutic(s) include a characteristic lipid-coated microbubble [LCM] subpopulation (i.e., a stable LCM suspension); such filmstabilized microbubbles are well known to substantially reduce the acoustic power levels needed for accomplishing temporary noninvasive (transcranial) ultrasound treatment, or sonoporation, if additionally desired for the Alzheimer's patient.

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Capillary dysfunction is associated with symptom severity and neurodegeneration in Alzheimer's disease

Abstract: Our results confirm the importance of microvascular pathology in AD. Deteriorating microvascular hemodynamics may cause hypoxia, which is known to precipitate amyloid retention.

Cited by 97 publications

References 44 publications

AAV-Syn-BDNF-EGFP Virus Construct Exerts Neuroprotective Action on the Hippocampal Neural Network during Hypoxia In Vitro

AAV-Syn-BDNF-EGFP Virus Construct Exerts Neuroprotective Action on the Hippocampal Neural Network during Hypoxia In Vitro

Implementing the proclamation of stroke and potentially preventable dementias

Nanotherapy for Early Dementia: Targeting Senile Dementia

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