Manual Acupuncture Regulates Behavior and Cerebral Blood Flow in the SAMP8 Mouse Model of Alzheimer’s Disease

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.

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Berberine Improves Cognitive Impairment by Simultaneously Impacting Cerebral Blood Flow and β-Amyloid Accumulation in an APP/tau/PS1 Mouse Model of Alzheimer’s Disease

Cells ◽

10.3390/cells10051161 ◽

2021 ◽

Vol 10 (5) ◽

pp. 1161

Author(s):

Chenghui Ye ◽

Yubin Liang ◽

Ying Chen ◽

Yu Xiong ◽

Yingfang She ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Blood Flow ◽

Cerebral Blood Flow ◽

Mouse Model ◽

Laser Speckle ◽

Cerebral Hypoperfusion ◽

Contrast Imaging ◽

Model Of Alzheimer’S Disease ◽

Β Amyloid

Alzheimer’s disease (AD) is accompanied by β-amyloid (Aβ), neurofibrillary tangles, and neuron cell death, and is one of the most commonly occurring diseases among the elderly. The pathology of AD is complex, involving Aβ overproduction and accumulation, tau hyperphosphorylation, and neuronal loss. In addition, chronic cerebral hypoperfusion (CCH) is ubiquitous in the AD patients and plans a pivotal role in triggering and exacerbating the pathophysiological progress of AD. The goal of this study was to investigate the neuroprotective properties of berberine (BBR) and the underlying mechanism. During the study, BBR was administrated to treat the triple-transgenic mouse model of Alzheimer’s disease (3×Tg AD). To thoroughly evaluate the effects of the BBR administration, multiple manners were utilized, for instance, 3D arterial spin labeling technique, Morris water maze assay, immunofluorescence staining, TUNEL assay, laser speckle contrast imaging, western blotting, etc. The results showed that BBR ameliorated cognitive deficits in 3×Tg AD mice, reduced the Aβ accumulation, inhibited the apoptosis of neurons, promoted the formation of microvessels in the mouse brain by enhancing brain CD31, VEGF, N-cadherin, Ang-1. The new vessels promoted by BBR were observed to have a complete structure and perfect function, which in turn promoted the recovery of cerebral blood flow (CBF). In general, berberine is effective to 3×Tg AD mice, has a neuroprotective effect, and is a candidate drug for the multi-target prevention and treatment of AD.

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Hypertension Impairs Cerebral Blood Flow in a Mouse Model for Alzheimer’s Disease

Current Alzheimer Research ◽

10.2174/1567205012666151027130135 ◽

2015 ◽

Vol 12 (10) ◽

pp. 914-922 ◽

Cited By ~ 14

Author(s):

Maximilian Wiesmann ◽

Carmen Capone ◽

Valerio Zerbi ◽

Laura Mellendijk ◽

Arend Heerschap ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Blood Flow ◽

Cerebral Blood Flow ◽

Mouse Model

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SPINGOSINE-1-PHOSPHATE RECEPTOR 5 AGONIST α-971432 IMPROVES LEARNING AND MEMORY IN THE SAMP8 MOUSE MODEL OF ALZHEIMER’S DISEASE

Alzheimer s & Dementia ◽

10.1016/j.jalz.2017.06.1862 ◽

2017 ◽

Vol 13 (7) ◽

pp. P949

Author(s):

Susan A. Farr ◽

Elizabeth Louise van der Kam ◽

Jordan W. Brown ◽

Michael L. Niehoff ◽

John E. Morley

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Mouse Model ◽

Learning And Memory ◽

Samp8 Mouse ◽

Model Of Alzheimer’S Disease

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Mitochondrial Superoxide Contributes to Blood Flow and Axonal Transport Deficits in the Tg2576 Mouse Model of Alzheimer's Disease

PLoS ONE ◽

10.1371/journal.pone.0010561 ◽

2010 ◽

Vol 5 (5) ◽

pp. e10561 ◽

Cited By ~ 47

Author(s):

Cynthia A. Massaad ◽

Samir K. Amin ◽

Lingyun Hu ◽

Yuan Mei ◽

Eric Klann ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Blood Flow ◽

Mouse Model ◽

Axonal Transport ◽

Tg2576 Mouse ◽

Mitochondrial Superoxide ◽

Model Of Alzheimer’S Disease

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Increasing cerebral blood flow improves cognition into late stages in Alzheimer’s disease mice

Journal of Cerebral Blood Flow & Metabolism ◽

10.1177/0271678x19873658 ◽

2019 ◽

Vol 40 (7) ◽

pp. 1441-1452 ◽

Cited By ~ 4

Author(s):

Oliver Bracko ◽

Brendah N Njiru ◽

Madisen Swallow ◽

Muhammad Ali ◽

Mohammad Haft-Javaherian ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Blood Flow ◽

Cerebral Blood Flow ◽

Short Term Memory ◽

Memory Function ◽

Neutrophil Adhesion ◽

Short Term ◽

Term Memory ◽

Model Of Alzheimer’S Disease

Alzheimer’s disease is associated with a 20–30% reduction in cerebral blood flow. In the APP/PS1 mouse model of Alzheimer’s disease, inhibiting neutrophil adhesion using an antibody against the neutrophil specific protein Ly6G was recently shown to drive rapid improvements in cerebral blood flow that was accompanied by an improvement in performance on short-term memory tasks. Here, in a longitudinal aging study, we assessed how far into disease development a single injection of anti-Ly6G treatment can acutely improve short-term memory function. We found that APP/PS1 mice as old as 15–16 months had improved performance on the object replacement and Y-maze tests of spatial and working short-term memory, measured at one day after anti-Ly6G treatment. APP/PS1 mice at 17–18 months of age or older did not show acute improvements in cognitive performance, although we did find that capillary stalls were still reduced and cerebral blood flow was still increased by 17% in 21–22-months-old APP/PS1 mice given anti-Ly6G antibody. These data add to the growing body of evidence suggesting that cerebral blood flow reductions are an important contributing factor to the cognitive dysfunction associated with neurodegenerative disease. Thus, interfering with neutrophil adhesion could be a new therapeutic approach for Alzheimer’s disease.

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