scholarly journals Hippocampus has lower oxygenation and weaker control of brain blood flow than cortex, due to microvascular differences

2019 ◽  
Author(s):  
K. Shaw ◽  
L. Bell ◽  
K. Boyd ◽  
D.M. Grijseels ◽  
D. Clarke ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Blood Flow ◽  
Cell Function ◽  
Regional Blood Flow ◽  
Blood Oxygenation ◽  
Endothelial Cell Function ◽  
Function Modelling ◽  
Visual Cortical

AbstractThe hippocampus is essential for spatial and episodic memory but is damaged early in Alzheimer’s disease and is very sensitive to hypoxia. Understanding how it regulates its oxygen supply is therefore key for designing interventions to preserve its function. However, studies of neurovascular function in the hippocampus in vivo have been limited by its relative inaccessibility. Here we compared hippocampal and visual cortical neurovascular function in awake mice, using two photon imaging of individual neurons and vessels and measures of regional blood flow and haemoglobin oxygenation. We show that blood flow, blood oxygenation and neurovascular coupling were decreased in the hippocampus compared to neocortex, because of differences in both the vascular network and pericyte and endothelial cell function. Modelling oxygen diffusion indicates that these features of the hippocampal vasculature could explain its sensitivity to damage during neurological conditions, including Alzheimer’s disease, where the brain’s energy supply is decreased.

scholarly journals Neurovascular coupling and oxygenation are decreased in hippocampus compared to neocortex because of microvascular differences

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
K. Shaw ◽  
L. Bell ◽  
K. Boyd ◽  
D. M. Grijseels ◽  
D. Clarke ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Blood Flow ◽  
Cell Function ◽  
Regional Blood Flow ◽  
Neurovascular Coupling ◽  
Blood Oxygenation ◽  
Endothelial Cell Function ◽  
Function Modelling

AbstractThe hippocampus is essential for spatial and episodic memory but is damaged early in Alzheimer’s disease and is very sensitive to hypoxia. Understanding how it regulates its oxygen supply is therefore key for designing interventions to preserve its function. However, studies of neurovascular function in the hippocampus in vivo have been limited by its relative inaccessibility. Here we compared hippocampal and visual cortical neurovascular function in awake mice, using two photon imaging of individual neurons and vessels and measures of regional blood flow and haemoglobin oxygenation. We show that blood flow, blood oxygenation and neurovascular coupling were decreased in the hippocampus compared to neocortex, because of differences in both the vascular network and pericyte and endothelial cell function. Modelling oxygen diffusion indicates that these features of the hippocampal vasculature may restrict oxygen availability and could explain its sensitivity to damage during neurological conditions, including Alzheimer’s disease, where the brain’s energy supply is decreased.

scholarly journals Regional HmPAO SPECT and CT Measurements in the Diagnosis of Alzheimer's Disease

1997 ◽  
Vol 24 (1) ◽  
pp. 22-28 ◽  
Author(s):  
A. Mattman ◽  
H. Feldman ◽  
B. Forste ◽  
D. Li ◽  
I. Szasz ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Blood Flow ◽  
Diagnostic Test ◽  
Discriminant Function ◽  
Regional Blood Flow ◽  
Cortical Atrophy ◽  
Stepwise Discriminant Analysis ◽  
Emission Computed Tomography ◽  
Hmpao Spect

ABSTRACT:Background:This study investigated the hypothesis that the combination of regional CT brain atrophy measurements and semiquantitative SPECT regional blood flow ratios could produce a diagnostic test for Alzheimer's disease (AD) with an accuracy comparable to that achieved with the present clinical gold standard of the NINCDS-ADRDA criteria.Methods:Single proton emission computed tomography (SPECT) and CT head scans were performed on 122 subjects referred an UBC Alzheimer clinic and diagnosed as either ‘not demented’ (ND-37) or ‘possible/probable AD’ (AD-85) by the NINCDS-ADRDA criteria. Stepwise discriminant analysis (SDA) was performed on the bilateral SPECT regions of interest and compared to bilateral CT qualitative/quantitative assessment in the frontal, parietal and temporal lobes to determine which were most accurate at ND/AD distinction. Receiver operating curves (ROC) were then constructed for these variables individually and for their combined discriminant function.Results:The left temporal qualitative cortical atrophy score (CT) and left temporal perfusion ratio (SPECT) were selected in the SDA. The combined discriminant function was more specific at AD/ND distinction than either of CT or SPECT alone. The accuracy of AD/ND distinction with the combined discriminant function was below that achieved by clinical diagnosis according to the NINCDS-ADRDA criteria and was not significantly different from that achieved with SPECT or CT alone as defined by ROC curve analysis.Conclusion:The measurements of left temporal cortical atrophy and regional cerebral blood flow were most indicative of AD; however they lacked the sensitivity and specificity to recommend their use as a diagnostic test for AD.

scholarly journals The Alzheimer’s disease protective R522 variant of PLCg2, consistently enhances PLCγ2 activation, depleting PI(4,5)P 2 levels and altering cell function in in vitro and in vivo assays

2020 ◽  
Vol 16 (S3) ◽  
Author(s):  
Thomas Ernest James Philips ◽  
Emily Maguire ◽  
Georgina E Menzies ◽  
Michael Sasner ◽  
Harriet M Williams ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cell Function ◽  
In Vivo Assays ◽  
Plcγ2 Activation

scholarly journals The Alzheimer’s disease protective P522R variant of PLCG2, consistently enhances stimulus-dependent PLCγ2 activation, depleting substrate and altering cell function

2020 ◽  
Author(s):  
Emily Maguire ◽  
Georgina E. Menzies ◽  
Thomas Phillips ◽  
Michael Sasner ◽  
Harriet M. Williams ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cell Function ◽  
Association Studies ◽  
Dynamic Modelling ◽  
Genome Wide Association Studies ◽  
Aβ Oligomers ◽  
Induced Pluripotent ◽  
Receptor Ligation

AbstractRecent genome-wide association studies of Alzheimer’s disease (AD) have identified variants implicating immune pathways in disease development. A rare coding variant of PLCG2, which encodes PLCγ2, shows a significant protective effect for AD (rs72824905, P522R, P=5.38×10−10, Odds Ratio = 0.68). Molecular dynamic modelling of the PLCγ2-R522 variant, situated within the auto-inhibitory domain of PLCγ2, suggests a structural change to the protein. Through CRISPR-engineering we have generated novel PLCG2-R522 harbouring human induced pluripotent cell lines (hiPSC) and a mouse knockin model, neither of which exhibits alterations in endogenous PLCG2 expression. Mouse microglia and macrophages and hiPSC-derived microglia-like cells with the R522 mutation, all demonstrate a consistent non-redundant hyperfunctionality in the context of normal expression of other PLC isoforms. This signalling alteration manifests as enhanced cellular Ca2+ store release (∼20-40% increase) in response to physiologically-relevant stimuli (e.g. Fc receptor ligation and Aβ oligomers). This hyperfunctionality resulted in increased PIP2 depletion in the cells with the PLCγ2-R522 variant after exposure to stimuli and reduced basal detection of PIP2 levels in vivo. These PLCγ2-R522 associated abnormalities resulted in impairments to phagocytosis (fungal and bacterial particles) and enhanced endocytosis (Aβ oligomers and dextran). PLCγ2 sits downstream of disease relevant pathways, such as TREM2 and CSF1R and alterations in its activity, direct impacts cell function, which in the context of the inherent drugability of enzymes such as PLCγ2, raise the prospect of manipulation of PLCγ2 as a therapeutic target in Alzheimer’s Disease.

scholarly journals PIP2 Improves Cerebral Blood Flow in a Mouse Model of Alzheimer’s Disease

Function ◽  
2021 ◽  
Vol 2 (2) ◽  
Author(s):  
Amreen Mughal ◽  
Osama F Harraz ◽  
Albert L Gonzales ◽  
David Hill-Eubanks ◽  
Mark T Nelson
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Mouse Model ◽  
Current Density ◽  
Functional Hyperemia ◽  
Model Of Alzheimer’S Disease ◽  
5Xfad Mice

Abstract Alzheimer’s disease (AD) is a leading cause of dementia and a substantial healthcare burden. Despite this, few treatment options are available for controlling AD symptoms. Notably, neuronal activity-dependent increases in cortical cerebral blood flow (CBF; functional hyperemia) are attenuated in AD patients, but the associated pathological mechanisms are not fully understood at the molecular level. A fundamental mechanism underlying functional hyperemia is activation of capillary endothelial inward-rectifying K+ (Kir2.1) channels by neuronally derived potassium (K+), which evokes a retrograde capillary-to-arteriole electrical signal that dilates upstream arterioles, increasing blood delivery to downstream active regions. Here, using a mouse model of familial AD (5xFAD), we tested whether this impairment in functional hyperemia is attributable to reduced activity of capillary Kir2.1 channels. In vivo CBF measurements revealed significant reductions in whisker stimulation (WS)-induced and K+-induced hyperemic responses in 5xFAD mice compared with age-matched controls. Notably, measurements of whole-cell currents in freshly isolated 5xFAD capillary endothelial cells showed that Kir2.1 current density was profoundly reduced, suggesting a defect in Kir2.1 function. Because Kir2.1 activity absolutely depends on binding of phosphatidylinositol 4,5-bisphosphate (PIP2) to the channel, we hypothesized that capillary Kir2.1 channel impairment could be corrected by exogenously supplying PIP2. As predicted, a PIP2 analog restored Kir2.1 current density to control levels. More importantly, systemic administration of PIP2 restored K+-induced CBF increases and WS-induced functional hyperemic responses in 5xFAD mice. Collectively, these data provide evidence that PIP2-mediated restoration of capillary endothelial Kir2.1 function improves neurovascular coupling and CBF in the setting of AD.

The effect of cholinesterase inhibitors on the regional blood flow in patients with Alzheimer's disease and vascular dementia

2003 ◽  
Vol 216 (1) ◽  
pp. 119-126 ◽  
Author(s):  
Wanda Lojkowska ◽  
Danuta Ryglewicz ◽  
Tomasz Jedrzejczak ◽  
Sławomira Minc ◽  
Teresa Jakubowska ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Blood Flow ◽  
Vascular Dementia ◽  
Cholinesterase Inhibitors ◽  
Regional Blood Flow
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