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Amyloid… Friend or Foe?

MISUNDERSTOOD

 

There is a longstanding hypothesis in research that beta amyloid- a build up of abnormally folded proteins- is responsible for Alzheimer’s disease.  The theory is that a build up of amyloid blocks the flow of nutrients in and out of the cells, thereby causing their death.  Researchers have spent years and years trying to reduce the amount of amyloid in the body, despite a poor correlation between the amount of amyloid in the brain and the level of dementia.  There is no question that there is a high level of amyloid build-up present in Alzheimer’s brains, but does its presence indicate that it’s the responsible party?  Or is it an innocent bystander- the unfortunate aftermath of some violent cell insult caused by a different evil force?   After 20 years of insufficient proof that amyloid is the cause, it’s time to look somewhere else.

There’s a new theory in town, well maybe not new, but gaining momentum… amyloid may not be culprit, but the byproduct of oxidative stress.  And even more interesting to consider, it may actually have a protective function against further cell death.  According to my internet research (actual references below), beta amyloid does do some good in the world… including activation of kinase enzymes, regulation of cholesterol transport, functioning as a transcription factor, and anti-microbial activity (potentially associated with beta amyloid’s pro-inflammatory activity).   Since it is impossible to target brain amyloid versus, say, amyloid lining our blood vessels, it is difficult to design a drug that won’t systemically alter the behavior of all amyloid.

So in theory, reducing the oxidative stress will reduce the excessive build up of amyloid…. and reduce neural cell death.

In considering all the hype about free radicals, antioxidants, and inflammation… it seems that many chronic diseases have these elements in common.  Until we know better, I think it’s a reasonable assumption that a healthy diet and good cardiovascular health would only play positive roles in this disease scenario- research pitfalls and all.

Here are some interesting research articles for your reading pleasure.

Reexamining Alzheimer’s disease: evidence for a protective role for amyloid-beta protein precursor and amyloid-beta.  

Amyloid Deposits: Protection Against Toxic Protein Species?

Bogoyevitch MA, Boehm I, Oakley A, Ketterman AJ, Barr RK (March 2004). “Targeting the JNK MAPK cascade for inhibition: basic science and therapeutic potential”. Biochim. Biophys. Acta 1697 (1–2): 89–101. doi:10.1016/j.bbapap.2003.11.016. PMID 15023353.

Tabaton M, Zhu X, Perry G, Smith MA, Giliberto L (January 2010). “Signaling Effect of Amyloid-β42 on the Processing of AβPP”. Exp. Neurol. 221 (1): 18–25. doi:10.1016/j.expneurol.2009.09.002. PMC 2812589. PMID 19747481.

Zou K, Gong JS, Yanagisawa K, Michikawa M (June 2002). “A novel function of monomeric amyloid beta-protein serving as an antioxidant molecule against metal-induced oxidative damage”. J. Neurosci. 22 (12): 4833–41. PMID 12077180.

Baruch-Suchodolsky R, Fischer B (May 2009). “Abeta40, either soluble or aggregated, is a remarkably potent antioxidant in cell-free oxidative systems”. Biochemistry 48 (20): 4354–70. doi:10.1021/bi802361k. PMID 19320465.

Yao ZX, Papadopoulos V (October 2002). “Function of beta-amyloid in cholesterol transport: a lead to neurotoxicity”. FASEB J. 16 (12): 1677–9. doi:10.1096/fj.02-0285fje. PMID 12206998.

Igbavboa U, Sun GY, Weisman GA, He Y, Wood WG (August 2009). “Amyloid β-Protein Stimulates Trafficking of Cholesterol and Caveolin-1 from the Plasma Membrane to the Golgi Complex in Mouse Primary Astrocytes”. Neuroscience 162 (2): 328–38. doi:10.1016/j.neuroscience.2009.04.049. PMC 3083247. PMID 19401218.

Maloney B, Lahiri DK (June 2011). “The Alzheimer’s amyloid β-peptide (Aβ) binds a specific DNA Aβ-interacting domain (AβID) in the APP, BACE1, and APOE promoters in a sequence-specific manner: Characterizing a new regulatory motif”. Gene 488 (1–2): 1–12. doi:10.1016/j.gene.2011.06.004. PMC 3381326. PMID 21699964.

Bailey JA, Maloney B, Ge YW, Lahiri DK (June 2011). “Functional activity of the novel Alzheimer’s amyloid β-peptide interacting domain (AβID) in the APP and BACE1 promoter sequences and implications in activating apoptotic genes and in amyloidogenesis”. Gene 488 (1–2): 13–22. doi:10.1016/j.gene.2011.06.017. PMC 3372404. PMID 21708232.

Soscia SJ, Kirby JE, Washicosky KJ, Tucker SM, Ingelsson M, Hyman B, Burton MA, Goldstein LE, Duong S, Tanzi RE, Moir RD (2010). Bush, Ashley I.. ed. “The Alzheimer’s Disease-Associated Amyloid β-Protein Is an Antimicrobial Peptide”. PLoS ONE 5 (3): e9505. Bibcode 2010PLoSO…5.9505S. doi:10.1371/journal.pone.0009505. PMC 2831066. PMID 20209079.

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