Alzheimer's disease can be treated: Why the delay?

Goldsmith, Harry S.

doi:10.4103/sni.sni_116_17

Cited by 9 publications

(9 citation statements)

References 35 publications

(44 reference statements)

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“…In a limited series of experiments in severe AD patients, a piece of omentum, which is known to secrete angiogenic factors and encourage new vessel growth, was surgically placed on the surface of the brain. In the patients that showed an increased CBF as a result, there were signs of improved cognitive function 5,43 Accordingly, improving CBF by interfering with neutrophil adhesion could be a promising therapeutic approach for AD.…”

Section: Discussionmentioning

confidence: 99%

Neutrophil adhesion in brain capillaries reduces cortical blood flow and impairs memory function in Alzheimer’s disease mouse models

et al. 2019

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Cerebral blood flow (CBF) reductions in Alzheimer’s disease (AD) patients and related mouse models have been recognized for decades, but the underlying mechanisms and resulting consequences on AD pathogenesis remain poorly understood. In APP/PS1 and 5xFAD mice we found that an increased number of cortical capillaries had stalled blood flow as compared to wildtype animals, largely due to neutrophils that adhered in capillary segments and blocked blood flow. 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. This study identified a novel cellular mechanism that explains the majority of the CBF reduction seen in two mouse models of AD and demonstrated that improving CBF rapidly improved short-term memory function. Restoring cerebral perfusion by preventing neutrophil adhesion may provide a novel strategy for improving cognition in AD patients.

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Section: Discussionmentioning

confidence: 99%

Neutrophil adhesion in brain capillaries reduces cortical blood flow and impairs memory function in Alzheimer’s disease mouse models

et al. 2019

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“…11,12 In support of this, limited studies in AD patients where a piece of omentum was surgically placed on the brain surface led to increased brain blood flow that was correlated to improvements in memory function. 54…”

Section: Discussionmentioning

confidence: 99%

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

Bracko

Njiru

Swallow

et al. 2019

J Cereb Blood Flow Metab

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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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“…In a limited series of experiments in severe AD patients, a piece of omentum, which is known to secrete angiogenic factors and encourage new vessel growth, was surgically placed on the surface of the brain. In the patients that showed an increased CBF as a result, there were signs of improved cognitive function 5,39 . Accordingly, improving CBF by interfering with neutrophil adhesion could be a promising therapeutic approach for AD.…”

Section: Discussionmentioning

confidence: 99%

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

Hernández

Bracko

Kersbergen

et al. 2017

Preprint

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Abstract:The 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.

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Alzheimer's disease can be treated: Why the delay?

Cited by 9 publications

References 35 publications

Neutrophil adhesion in brain capillaries reduces cortical blood flow and impairs memory function in Alzheimer’s disease mouse models

Neutrophil adhesion in brain capillaries reduces cortical blood flow and impairs memory function in Alzheimer’s disease mouse models

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

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

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