scholarly journals Neutrophil adhesion in brain capillaries contributes to cortical blood flow decreases and impaired memory function in a mouse model of Alzheimer’s disease

2017 ◽  
Author(s):  
Jean C. Cruz Hernández ◽  
Oliver Bracko ◽  
Calvin J. Kersbergen ◽  
Victorine Muse ◽  
Mohammad Haft-Javaherian ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Blood Flow ◽  
Mouse Model ◽  
Short Term Memory ◽  
Leukocyte Adhesion ◽  
Memory Function ◽  
Model Of Alzheimer’S Disease ◽  
Improved Performance ◽  
Novel Strategy

AbstractThe existence of cerebral blood flow (CBF) reductions in Alzheimer’s disease (AD) patients and related mouse models has been known for decades, but the underlying mechanisms and the resulting impacts on cognitive function and AD pathogenesis remain poorly understood. In the APP/PS1 mouse model of AD we found that an increased number of cortical capillaries had stalled blood flow as compared to wildtype animals, largely due to leukocytes that adhered in capillary segments and blocked blood flow. These capillary stalls were an early feature of disease development, appearing before amyloid deposits. Administration of antibodies against the neutrophil marker Ly6G reduced the number of stalled capillaries, leading to an immediate increase in CBF and to rapidly improved performance in spatial and working memory tasks. Our work has thus identified a cellular mechanism that explains the majority of the CBF reduction seen in a mouse model of AD and has also demonstrated that improving CBF rapidly improved short-term memory function. Restoring cerebral perfusion by preventing the leukocyte adhesion that plugs capillaries may provide a novel strategy for improving cognition in AD patients.

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

2019 ◽  
Vol 40 (7) ◽  
pp. 1441-1452 ◽  
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.

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

2019 ◽  
Author(s):  
Oliver Bracko ◽  
Brendah N. Njiru ◽  
Madisen Swallow ◽  
Muhammad Ali ◽  
Chris B. Schaffer
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Short Term Memory ◽  
Memory Function ◽  
Specific Protein ◽  
Short Term ◽  
Term Memory ◽  
Improved Performance

AbstractAlzheimer’s disease (AD) is associated with a 20-30% reduction in cerebral blood flow. In the APP/PS1 mouse model of AD, 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 can acutely improve 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 short-term memory, measured at one day after anti-Ly6G treatment. APP/PS1 mice 17-18 months of age or older did not show acute improvements in cognitive performance, although we did find that cerebral blood flow was still increased by 17% in 21-22 months old APP/PS1 mice given anti-Ly6G. 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.

scholarly journals A pilot study investigating the effects of voluntary exercise on capillary stalling and cerebral blood flow in the APP/PS1 mouse model of Alzheimer’s disease

PLoS ONE ◽  
2020 ◽  
Vol 15 (8) ◽  
pp. e0235691
Author(s):  
Kaja Falkenhain ◽  
Nancy E. Ruiz-Uribe ◽  
Mohammad Haft-Javaherian ◽  
Muhammad Ali ◽  
Pietro E. Michelucci ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Pilot Study ◽  
Mouse Model ◽  
Voluntary Exercise ◽  
Model Of Alzheimer’S Disease

Metformin Treatment Alters Memory Function in a Mouse Model of Alzheimer's Disease

2015 ◽  
Vol 44 (1) ◽  
pp. 43-48 ◽  
Author(s):  
Kacee A. DiTacchio ◽  
Stephen F. Heinemann ◽  
Gustavo Dziewczapolski
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Memory Function ◽  
Metformin Treatment ◽  
Model Of Alzheimer’S Disease

P4-097: Stalled Blood flow in Brain Capillaries is Responsible for Reduced Cortical Perfusion in a Mouse Model of Alzheimer’s Disease

2016 ◽  
Vol 12 ◽  
pp. P1049-P1050 ◽  
Author(s):  
Jean C. Cruz Hernandez ◽  
Calvin Kersbergen ◽  
Victorine Muse ◽  
Iryna Ivasyk ◽  
Oliver Bracko ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Blood Flow ◽  
Mouse Model ◽  
Brain Capillaries ◽  
Model Of Alzheimer’S Disease ◽  
Cortical Perfusion

Ca2+-permeable TRPV1 pain receptor knockout rescues memory deficits and reduces amyloid-β and tau in a mouse model of Alzheimer’s disease

2019 ◽  
Vol 29 (2) ◽  
pp. 228-237 ◽  
Author(s):  
Juyong Kim ◽  
Siyoung Lee ◽  
Jaekyoon Kim ◽  
Sangwoo Ham ◽  
Jung Han Yoon Park ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Nervous System ◽  
Mouse Model ◽  
Transient Receptor Potential ◽  
Memory Function ◽  
Amyloid Β ◽  
Neuronal Cultures ◽  
Transient Receptor Potential Vanilloid ◽  
Model Of Alzheimer’S Disease

Abstract The transient receptor potential vanilloid 1 (TRPV1) protein is a pain receptor that elicits a hot sensation when an organism eats the capsaicin of red chili peppers. This calcium (Ca2+)-permeable cation channel is mostly expressed in the peripheral nervous system sensory neurons but also in the central nervous system (e.g. hippocampus and cortex). Preclinical studies found that TRPV1 mediates behaviors associated with anxiety and depression. Loss of TRPV1 functionality increases expression of genes related to synaptic plasticity and neurogenesis. Thus, we hypothesized that TRPV1 deficiency may modulate Alzheimer’s disease (AD). We generated a triple-transgenic AD mouse model (3xTg-AD+/+) with wild-type (TRPV1+/+), hetero (TRPV1+/−) and knockout (TRPV1−/−) TRPV1 to investigate the role of TRPV1 in AD pathogenesis. We analyzed the animals’ memory function, hippocampal Ca2+ levels and amyloid-β (Aβ) and tau pathologies when they were 12 months old. We found that compared with 3xTg-AD−/−/TRPV1+/+ mice, 3xTg-AD+/+/TRPV1+/+ mice had memory impairment and increased levels of hippocampal Ca2+, Aβ and total and phosphorylated tau. However, 3xTg-AD+/+/TRPV1−/− mice had better memory function and lower levels of hippocampal Ca2+, Aβ, tau and p-tau, compared with 3xTg-AD+/+/TRPV1+/+ mice. Examination of 3xTg-AD-derived primary neuronal cultures revealed that the intracellular Ca2+ chelator BAPTA/AM and the TRPV1 antagonist capsazepine decreased the production of Aβ, tau and p-tau. Taken together, these results suggested that TRPV1 deficiency had anti-AD effects and promoted resilience to memory loss. These findings suggest that drugs or food components that modulate TRPV1 could be exploited as therapeutics to prevent or treat AD.

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