scholarly journals Deregulation of brain endothelial CD2AP in Alzheimer's disease impairs Reelin-mediated neurovascular coupling

2020 ◽  
Author(s):  
Milene Vandal ◽  
Colin Gunn ◽  
Adam Institoris ◽  
Philippe Bourassa ◽  
Ramesh C. Mishra ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Vascular Dysfunction ◽  
Memory Function ◽  
Neurovascular Coupling ◽  
Functional Hyperemia ◽  
Brain Endothelium ◽  
Predisposing Factor ◽  
Brain Vessels ◽  
The Brain

Cerebrovascular dysfunction is increasingly recognized as a major contributor to Alzheimer's disease (AD). CD2-associated protein (CD2AP), an important predisposing factor for the disease, is enriched in the brain endothelium but the function of protein in the brain vasculature remains undefined. Here, we report that lower levels of CD2AP in brain vessels of human AD volunteers are associated with cognitive deficits. In awake mice, we show that brain endothelial CD2AP regulates cerebral blood flow during resting state and functional hyperemia. In the endothelium, CD2AP controls the levels and signaling of apolipoprotein E receptor 2 (ApoER2), a receptor activated by Reelin glycoprotein that is linked to memory function. Further, Reelin promotes brain vessel dilation and functional hyperemia and both effects are modulated by endothelial CD2AP. Finally, lower levels of ApoER2 in brain vessels are associated with vascular defects and cognitive dysfunction in AD individuals. Thus, deregulation of CD2AP impairs neurovascular coupling and harnessing the biology of the Reelin-ApoER2-CD2AP signaling axis in the brain endothelium may improve brain vascular dysfunction in AD patients.

scholarly journals Assessment of neurovascular coupling and cortical spreading depression in mixed mouse models of atherosclerosis and Alzheimer’s disease

eLife ◽  
2022 ◽  
Vol 11 ◽  
Author(s):  
Osman Shabir ◽  
Ben Pendry ◽  
Llywelyn Lee ◽  
Beth Eyre ◽  
Paul S Sharp ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cortical Spreading Depression ◽  
Mixed Model ◽  
Spreading Depression ◽  
Neurovascular Coupling ◽  
Cardiovascular Comorbidities ◽  
Neurological Conditions ◽  
Electrode Insertion ◽  
The Brain

Neurovascular coupling is a critical brain mechanism whereby changes to blood flow accompany localised neural activity. The breakdown of neurovascular coupling is linked to the development and progression of several neurological conditions including dementia. In this study, we examined cortical haemodynamics in mouse preparations that modelled Alzheimer’s disease (J20-AD) and atherosclerosis (PCSK9-ATH) between 9 and 12 m of age. We report novel findings with atherosclerosis where neurovascular decline is characterised by significantly reduced blood volume, altered levels of oxyhaemoglobin and deoxyhaemoglobin, in addition to global neuroinflammation. In the comorbid mixed model (J20-PCSK9-MIX), we report a 3 x increase in hippocampal amyloid-beta plaques. A key finding was that cortical spreading depression (CSD) due to electrode insertion into the brain was worse in the diseased animals and led to a prolonged period of hypoxia. These findings suggest that systemic atherosclerosis can be detrimental to neurovascular health and that having cardiovascular comorbidities can exacerbate pre-existing Alzheimer’s-related amyloid-plaques.

scholarly journals GPCR19 regulates P2X7R-mediated NLRP3 inflammasomal activation of microglia by Amyloid β in Alzheimer’s diseases

2020 ◽  
Author(s):  
Jahirul Islam ◽  
Jung-Ah Cho ◽  
Ju-yong Kim ◽  
Kyung-Sun Park ◽  
Young-Jae koh ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Nlrp3 Inflammasome ◽  
Memory Function ◽  
Scavenger Receptor ◽  
Amyloid Β ◽  
Neuronal Loss ◽  
Priming Phase ◽  
5Xfad Mice ◽  
The Brain

Abstract Amyloid β (Aβ) and/or ATP activates NLRP3 inflammasome (N3I) by P2 × 7R ion channel of microglia, which is crucial in neuroinflammation shown in Alzheimer’s disease (AD). Due to polymorphisms, subtypes, and ubiquitous expression of P2 × 7R, inhibition of P2 × 7R has not been effective for AD. We first report that GPCR19 is a prerequisite for P2 × 7R-mediated N3I activation and Taurodeoxycholate (TDCA), a GPCR19 ligand, inhibited the priming phase of N3I activation, suppressed P2 × 7R expression and P2 × 7R-mediated Ca++ mobilization, and N3I oligomerization which is essential for production of IL-1β/IL-18. Further, TDCA increased expression of scavenger receptor (SR) A, enhanced phagocytosis of Aβ, and decreased Aβ plaque numbers in the brain of 5x Familial Alzheimer’s disease (5xFAD) mice. TDCA also reduced microgliosis, prevented neuronal loss, and improved memory function of 5xFAD mice. The pleiotropic roles of GPCR19 in P2 × 7-mediated N3I activation suggest that targeting GPCR19 might resolve neuroinflammation in AD patients.

scholarly journals The Impact of Meditation on the Cognitive Functions of Patients with Alzheimer’s Disease

2021 ◽  
Author(s):  
Maria Clara Lopes Rezende ◽  
Mariana Vanon Moreira ◽  
Bárbara Gomes Muffato ◽  
Yves Henrique Faria Dias ◽  
Ana Luíza Badini Tubenchlak ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Memory Function ◽  
Brain Network ◽  
Brain Structure And Function ◽  
Improve Sleep Quality ◽  
And Function ◽  
The Impact ◽  
The Brain ◽  
Positive Effect

Introduction: Alzheimer’s disease (AD) is the most common form of dementia, which has no cure and, also, effective therapies to prevent or slow the progression of AD remain elusive. Thus, it is necessary to find another way to treat this disease Objective: Investigate the impact of meditation on the cognitive function of patients with AD. Methods: In April 2021, a systematic review was carried out on MEDLINE using the descriptors: “Meditation” and “Alzheimer Disease” and their variations. Studies published in the last 10 years and in English were included. Results: Of the 40 articles found, four are part of this review. It was showed that meditation generates improvements in memory as it increases cerebral blood flow, stabilizes synapses and elevates important neurotransmitters. Aligned, it can improve sleep quality and retrospective memory function. Furthermore, daily practices help in neuropsychological conditions and generate beneficial changes in brain structure and function. Finally, it provokes changes in the brain network, such as the increased power of the theta band, involved in memory processes. Conclusion: The results imply a positive effect of meditation on patients with AD. However, further research is needed to confirm the validity of the results.

scholarly journals Identifying the Main Functional Pathways Associated with Cognitive Resilience to Alzheimer’s Disease

2021 ◽  
Vol 22 (17) ◽  
pp. 9120
Author(s):  
Marta Pérez-González ◽  
Sara Badesso ◽  
Elena Lorenzo ◽  
Elizabeth Guruceaga ◽  
Alberto Pérez-Mediavilla ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mononuclear Cells ◽  
Memory Function ◽  
Temporal Cortex ◽  
Mrna Levels ◽  
Peripheral Blood Mononuclear ◽  
Novel Treatments ◽  
Peripheral Immune Cells ◽  
The Brain

Understanding the mechanisms involved in cognitive resilience in Alzheimer’s disease (AD) represents a promising strategy to identify novel treatments for dementia in AD. Previous findings from our group revealed that the study of aged-Tg2576 cognitive resilient individuals is a suitable tool for this purpose. In the present study, we performed a transcriptomic analysis using the prefrontal cortex of demented and resilient Tg2576 transgenic AD mice. We have been able to hypothesize that pathways involved in inflammation, amyloid degradation, memory function, and neurotransmission may be playing a role on cognitive resilience in AD. Intriguingly, the results obtained in this study are suggestive of a reduction of the influx of peripheral immune cells into the brain on cognitive resilient subjects. Indeed, Cd4 mRNA expression is significantly reduced on Tg2576 mice with cognitive resilience. For further validation of this result, we analyzed CD4 expression in human AD samples, including temporal cortex and peripheral blood mononuclear cells (PBMC). Interestingly, we have found a negative correlation between CD4 mRNA levels in the periphery and the score in the Mini-Mental State Exam of AD patients. These findings highlight the importance of understanding the role of the immune system on the development of neurodegenerative diseases and points out to the infiltration of CD4+ cells in the brain as a key player of cognitive dysfunction in AD.

scholarly journals Assessment of Neurovascular Coupling & Cortical Spreading Depression in Mixed Models of Atherosclerosis & Alzheimer’s Disease

2020 ◽  
Author(s):  
Osman Shabir ◽  
Ben Pendry ◽  
Llywelyn Lee ◽  
Beth Eyre ◽  
Paul Sharp ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neural Activity ◽  
Cortical Spreading Depression ◽  
Spreading Depression ◽  
Neurovascular Coupling ◽  
Disease Models ◽  
Brain State ◽  
The Brain ◽  
Dementia Onset

AbstractNeurovascular coupling is a critical brain mechanism whereby changes to blood flow accompany localised neural activity. The breakdown of neurovascular coupling is linked to the development and progression of several neurological conditions including dementia. However, experimental data commonly arise from preclinical models in young mice with one disease only. In this study, we examined cortical haemodynamics in preparations that modelled common co-existing conditions namely Alzheimer’s disease (J20-AD) combined with atherosclerosis (PCSK9-ATH) between 9-12m of age. We report novel findings with atherosclerosis where neurovascular decline is characterised by significantly reduced blood volume (HbT), levels of oxyhaemoglobin (HbO) & deoxyhaemoglobin (HbR), in addition to global neuroinflammation. In the comorbid mixed model (J20-PCSK9-MIX), we report a highly significant increase (3x fold) in hippocampal amyloid-beta plaques, without any further alterations to neurovascular function. There were no significant changes in evoked neural activity in any of the disease models, suggesting a breakdown of neurovascular coupling in PCSK9-ATH mice with inadequate oxygen delivery. A key finding was that cortical spreading depression (CSD) due to electrode insertion into the brain was worse in the diseased animals and led to a prolonged period of hypoxia and potentially ischaemia. The inflammatory environment in the brain was also perturbed, with interleukin-1 beta raised up to 2-fold and tumour necrosis factor raised up to 7-fold in brain tissues from these mice. Taken together, these findings suggest that systemic atherosclerosis can be detrimental to neurovascular health and that having cardiovascular comorbidities can exacerbate pre-existing Alzheimer’s-related amyloid-plaques.Significance StatementThe development of therapies for dementia is one of the biggest scientific priorities as many amyloid-targeting treatments have failed clinical trials in the past, and to date, we have no disease modifying therapies. Understanding the different disease mechanisms involved in the onset of dementia is important if therapies are to succeed. Evidence has pointed to vascular dysfunction as a key potential mechanism involved in dementia onset and many preclinical studies have highlighted the role of impaired neurovascular coupling in such models. In this study we report novel findings with respect to neurovascular dysfunction in disease models, as well as describing how brain state plays a role in worsened outcomes of brain injury and migraine in the context of dementia onset.

scholarly journals Alzheimer’s Disease—Rationales for Potential Treatment with the Thrombin Inhibitor Dabigatran

2021 ◽  
Vol 22 (9) ◽  
pp. 4805
Author(s):  
Klaus Grossmann
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Vascular Dysfunction ◽  
Amyloid Β ◽  
Brain Parenchyma ◽  
Thrombin Inhibitor ◽  
Amyloid Angiopathy ◽  
Barrier Dysfunction ◽  
Neuron Death ◽  
The Brain

Alzheimer’s disease (AD) is caused by neurodegenerative, but also vascular and hemostatic changes in the brain. The oral thrombin inhibitor dabigatran, which has been used for over a decade in preventing thromboembolism and has a well-known pharmacokinetic, safety and antidote profile, can be an option to treat vascular dysfunction in early AD, a condition known as cerebral amyloid angiopathy (CAA). Recent results have revealed that amyloid-β proteins (Aβ), thrombin and fibrin play a crucial role in triggering vascular and parenchymal brain abnormalities in CAA. Dabigatran blocks soluble thrombin, thrombin-mediated formation of fibrin and Aβ-containing fibrin clots. These clots are deposited in brain parenchyma and blood vessels in areas of CAA. Fibrin-Aβ deposition causes microvascular constriction, occlusion and hemorrhage, leading to vascular and blood–brain barrier dysfunction. As a result, blood flow, perfusion and oxygen and nutrient supply are chronically reduced, mainly in hippocampal and neocortical brain areas. Dabigatran has the potential to preserve perfusion and oxygen delivery to the brain, and to prevent parenchymal Aβ-, thrombin- and fibrin-triggered inflammatory and neurodegenerative processes, leading to synapse and neuron death, and cognitive decline. Beneficial effects of dabigatran on CAA and AD have recently been shown in preclinical studies and in retrospective observer studies on patients. Therefore, clinical studies are warranted, in order to possibly expand dabigatran approval for repositioning for AD treatment.

scholarly journals Syndapin-2 Mediates Amyloid-β Transcytosis at the Brain Endothelium: Implications in Alzheimer’s Disease

2020 ◽  
Author(s):  
Diana M. Leite ◽  
Mohsen Seifi ◽  
Jerome D. Swinny ◽  
Giuseppe Battaglia
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Low Density Lipoprotein ◽  
Amyloid Β ◽  
Density Lipoprotein ◽  
Amyloid Angiopathy ◽  
Brain Endothelium ◽  
Endosomal Sorting ◽  
Density Lipoprotein Receptor ◽  
The Brain

A faulty transport of amyloid-β (Aβ) across the blood-brain barrier (BBB), and its diminished clearance from the brain, contributes to neurodegenerative and vascular pathologies, including Alzheimer’s disease (AD) and cerebral amyloid angiopathy, respectively. At the BBB, Aβ efflux transport is associated with the low-density lipoprotein receptor-related protein 1 (LRP1). However, the precise mechanisms governing the Aβ transport across the BBB, in health and disease, remain to be fully understood. New evidences suggest that LRP1 transcytosis occur through a tubular mechanism mediated by an F-BAR protein, syndapin-2. We show here that syndapin-2 is associated with Aβ clearance across the BBB. We further demonstrate whether risk factors for AD, Aβ expression and ageing, impact on native syndapin-2 expression in the brain endothelium, with syndapin-2 mediating Aβ transcytosis. Both increased Aβ expression and ageing significantly decreased expression of syndapin-2. These are mirrored by an alteration of the endosome-associated protein Rab5, with an increase of expression with Aβ accumulation and ageing. Collectively, our data reveal that the syndapin-2-mediated pathway and its balance with endosomal sorting at endothelial level are critical for the clearance of neuronally-derived Aβ, and thus proposing a new measure to assess AD and ageing, as well as, a potential target for counteracting the build-up of brain Aβ.

scholarly journals Enhanced Cerebral Blood Volume under Normobaric Hyperoxia in the J20-hAPP Mouse Model of Alzheimer’s Disease

2019 ◽  
Author(s):  
Osman Shabir ◽  
Paul Sharp ◽  
Monica A Rebollar ◽  
Luke Boorman ◽  
Clare Howarth ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Blood Volume ◽  
Neural Activity ◽  
Cerebral Blood Volume ◽  
Neurovascular Coupling ◽  
Cranial Window ◽  
Model Of Alzheimer’S Disease ◽  
The Brain

AbstractEarly impairments to neurovascular coupling have been proposed to be a key pathogenic factor in the onset and progression of Alzheimer’s disease (AD). Studies have shown impaired neurovascular function in several mouse models of AD, including the J20-hAPP mouse. In this study, we aimed to investigate early neurovascular changes using wild-type (WT) controls and J20-hAPP mice at 6-9 months of age, by measuring cerebral haemodynamics and neural activity to physiological sensory stimulations. A thinned cranial window was prepared to allow access to cortical vasculature and imaged using 2D-optical imaging spectroscopy (2D-OIS). After chronic imaging sessions where the skull was intact, a terminal acute imaging session was performed where an electrode was inserted into the brain to record simultaneous neural activity. We found that cerebral haemodynamic changes were significantly enhanced in J20-hAPP mice compared with controls in response to physiological stimulations, potentially due to the significantly higher neural activity (hyperexcitability) seen in the J20-hAPP mice. Thus, neurovascular coupling remained preserved under a chronic imaging preparation. Further, under hyperoxia, the baseline blood volume and saturation of all vascular compartments in the brains of J20-hAPP mice were substantially enhanced compared to WT controls, but this effect disappeared under normoxic conditions. This study highlights novel findings not previously seen in the J20-hAPP mouse model, and may point towards a potential therapeutic strategy by driving an increased baseline blood flow to the brain, thereby potentially enhancing the clearance of beta-amyloid.

Longitudinal Changes in Individual BrainAGE in Healthy Aging, Mild Cognitive Impairment, and Alzheimer’s Disease

GeroPsych ◽  
2012 ◽  
Vol 25 (4) ◽  
pp. 235-245 ◽  
Author(s):  
Katja Franke ◽  
Christian Gaser
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Healthy Aging ◽  
Brain Aging ◽  
Elderly Subjects ◽  
Additional Increase ◽  
Longitudinal Changes ◽  
Novel Method ◽  
The Brain

We recently proposed a novel method that aggregates the multidimensional aging pattern across the brain to a single value. This method proved to provide stable and reliable estimates of brain aging – even across different scanners. While investigating longitudinal changes in BrainAGE in about 400 elderly subjects, we discovered that patients with Alzheimer’s disease and subjects who had converted to AD within 3 years showed accelerated brain atrophy by +6 years at baseline. An additional increase in BrainAGE accumulated to a score of about +9 years during follow-up. Accelerated brain aging was related to prospective cognitive decline and disease severity. In conclusion, the BrainAGE framework indicates discrepancies in brain aging and could thus serve as an indicator for cognitive functioning in the future.

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