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The Possibility of Reducing Amyloid in the Brain by Reducing it Elsewhere

This paper explores the mechanisms by which the amyloid associated with the progression of Alzheimer's disease can be cleared naturally outside the brain. It raises the possibility that finding ways to reduce amyloid outside the brain will allow existing transport and clearance mechanisms to export and remove more of the amyloid from the brain. A counter-argument to this hypothesis is that these transport and clearance mechanisms become damaged and dysfunctional with age. There are, for example, research groups examining the drainage of cerebrospinal fluid, one of the ways in which amyloid might leave the brain, who have found this fluid flow diminished in Alzheimer's patients. There is similar work on age-related declines in the mechanisms for filtration of cerebrospinal fluid that are located in the choroid plexus. It is a still open question as to the degree that these various mechanisms - and others - contribute to the overall progression of Alzheimer's disease. The best way to answer that question is to repair individual suspected causes one at a time, and see what happens as a result.

Alzheimer's disease (AD) is the most common form of dementia among the elderly. Senile plaques containing amyloid-beta protein (Aβ) in the brain are a pathological hallmark of AD and they play a pivotal role in AD pathogenesis. The steady-state level of Aβ in the brain is determined by the balance between Aβ production and its clearance. In the brain, Aβ can be cleared via microglial phagocytosis and proteolytic degradation by enzymes such as neprilysin (NEP) and insulin-degrading enzyme (IDE). Transport of Aβ from the brain into the peripheral blood has been demonstrated in both animal models and humans. There are several potential pathways for the efflux of brain Aβ into the periphery. These include transport across the blood-brain barrier (BBB) mediated by low-density lipoprotein receptor-related peptide 1 (LRP1), drainage from interstitial fluid (ISF) into cerebrospinal fluid (CSF) via perivascular or glymphatic pathways, reabsorption from CSF into the venous blood via arachnoid villi and blood-CSF barrier, or into the lymphatic system from the perivascular and perineural spaces, and possibly via meningeal lymphatic vessels.

The physiological capacity of peripheral tissues and organs in clearing brain-derived Aβ and its therapeutic potential for AD remains largely unknown. Here, we measured blood Aβ levels in different locations of the circulation in humans and mice, and used a parabiosis model to investigate the effect of peripheral Aβ catabolism on AD pathogenesis. We found that blood Aβ levels in the inferior/posterior vena cava were lower than that in the superior vena cava in both humans and mice. In addition, injected 125I labeled Aβ40 was located mostly in the liver, kidney, gastrointestinal tract, and skin but very little in the brain; suggesting that Aβ derived from the brain can be cleared in the periphery. Parabiosis before and after Aβ deposition in the brain significantly reduced brain Aβ burden without alterations in the expression of amyloid precursor protein, Aβ generating and degrading enzymes, Aβ transport receptors, and AD-type pathologies including hyperphosphorylated tau, neuroinflammation, as well as neuronal degeneration and loss in the brains of parabiotic AD mice. Our study revealed that the peripheral system is potent in clearing brain Aβ and preventing AD pathogenesis. The present work suggests that peripheral Aβ clearance is a valid therapeutic approach for AD, and implies that deficits in the Aβ clearance in the periphery might also contribute to AD pathogenesis.

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4575389/

Comments

This is largely my logic in donating blood five times a year, removal of accumulated unclearable 'junk' from the blood will allow similar junk from organs and tissues to leach into the blood until equilibrium is reestablished.

Posted by: JohnD at May 26th, 2016 1:27 PM

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