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 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 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.

scholarly journals Failure of the Brain Glucagon-Like Peptide-1-Mediated Control of Intestinal Redox Homeostasis in a Rat Model of Sporadic Alzheimer’s Disease

Antioxidants ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1118
Author(s):  
Jan Homolak ◽  
Ana Babic Perhoc ◽  
Ana Knezovic ◽  
Jelena Osmanovic Barilar ◽  
Melita Salkovic-Petrisic
Keyword(s):  
Oxidative Stress ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Rat Model ◽  
Redox Homeostasis ◽  
Brain State ◽  
Gastrointestinal Hormone ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
The Brain

The gastrointestinal system may be involved in the etiopathogenesis of the insulin-resistant brain state (IRBS) and Alzheimer’s disease (AD). Gastrointestinal hormone glucagon-like peptide-1 (GLP-1) is being explored as a potential therapy as activation of brain GLP-1 receptors (GLP-1R) exerts neuroprotection and controls peripheral metabolism. Intracerebroventricular administration of streptozotocin (STZ-icv) is used to model IRBS and GLP-1 dyshomeostasis seems to be involved in the development of neuropathological changes. The aim was to explore (i) gastrointestinal homeostasis in the STZ-icv model (ii) assess whether the brain GLP-1 is involved in the regulation of gastrointestinal redox homeostasis and (iii) analyze whether brain-gut GLP-1 axis is functional in the STZ-icv animals. Acute intracerebroventricular treatment with exendin-3(9-39)amide was used for pharmacological inhibition of brain GLP-1R in the control and STZ-icv rats, and oxidative stress was assessed in plasma, duodenum and ileum. Acute inhibition of brain GLP-1R increased plasma oxidative stress. TBARS were increased, and low molecular weight thiols (LMWT), protein sulfhydryls (SH), and superoxide dismutase (SOD) were decreased in the duodenum, but not in the ileum of the controls. In the STZ-icv, TBARS and CAT were increased, LMWT and SH were decreased at baseline, and no further increment of oxidative stress was observed upon central GLP-1R inhibition. The presented results indicate that (i) oxidative stress is increased in the duodenum of the STZ-icv rat model of AD, (ii) brain GLP-1R signaling is involved in systemic redox regulation, (iii) brain-gut GLP-1 axis regulates duodenal, but not ileal redox homeostasis, and iv) brain-gut GLP-1 axis is dysfunctional in the STZ-icv model.

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.

Brain glucose transporter protein 2 and sporadic Alzheimer’s disease

2010 ◽  
Vol 1 (3) ◽  
Author(s):  
Melita Šalković-Petrišić ◽  
Peter Riederer
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Glucose Transporter ◽  
Glucose Utilization ◽  
Brain State ◽  
Sporadic Alzheimer’S Disease ◽  
Insulin Resistant ◽  
Transporter Protein ◽  
Clinical Syndromes ◽  
The Brain

AbstractSporadic Alzheimer’s disease (sAD) is associated with decreased glucose/energy metabolism in the brain. The majority of glucose utilization in the brain appears to be mediated through glucose transporter protein 1 and 3 (GLUT1 and GLUT3). Deficiency of GLUT1 and GLUT3 in the brain has been found in sAD patients post mortem; however this is not unique to the disease as it is associated with different clinical syndromes as well. In line with recent findings that insulin resistant brain state precedes and may possibly cause sAD, an experimental sAD model based on the central application of the streptozotocin (STZ-icv rat model), which is a selective GLUT2 substrate, has drawn attention to the possible significance of the brain GLUT2 in sAD etiopathogenesis. Important steps in the GLUT2 and sAD interplay are reviewed and discussed. It is concluded that increased vulnerability of GLUT2 expressing neurons may be involved in development of sAD.

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.

The Weak Combined Magnetic Fields Reduce the Brain β-Amyloid in an Animal Model of Sporadic Alzheimer's Disease

PIERS Online ◽  
2009 ◽  
Vol 5 (4) ◽  
pp. 311-315 ◽  
Author(s):  
Natalia V. Bobkova ◽  
Vadim V. Novikov ◽  
Natalia I. Medvinskaya ◽  
Irina Yu. Aleksandrova ◽  
Eugenii E. Fesenko
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Animal Model ◽  
Magnetic Fields ◽  
Sporadic Alzheimer’S Disease ◽  
Combined Magnetic Fields ◽  
The Brain

SPECIFIC PROPERTIES OF TUBULIN IN THE PREFRONTAL CORTEX IN CONTROL, SCHIZOPHRENIA AND VASCULAR DEMENTIA

2020 ◽  
pp. 65-71
Author(s):  
Burbaeva G.Sh. ◽  
Androsova L.V. ◽  
Vorobyeva E.A. ◽  
Savushkina O.K.
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Prefrontal Cortex ◽  
Vascular Dementia ◽  
Binding Activity ◽  
Nephelometric Method ◽  
Rate Of Polymerization ◽  
Mental Diseases ◽  
And Control ◽  
The Brain

The aim of the study was to evaluate the rate of polymerization of tubulin into microtubules and determine the level of colchicine binding (colchicine-binding activity of tubulin) in the prefrontal cortex in schizophrenia, vascular dementia (VD) and control. Colchicine-binding activity of tubulin was determined by Sherlinе in tubulin-enriched extracts of proteins from the samples. Measurement of light scattering during the polymerization of the tubulin was carried out using the nephelometric method at a wavelength of 450-550 nm. There was a significant decrease in colchicine-binding activity and the rate of tubulin polymerization in the prefrontal cortex in both diseases, and in VD to a greater extent than in schizophrenia. The obtained results suggest that not only in Alzheimer's disease, but also in other mental diseases such as schizophrenia and VD, there is a decrease in the level of tubulin in the prefrontal cortex of the brain, although to a lesser extent than in Alzheimer's disease, and consequently the amount of microtubules.

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