Amyloid B Protein of Alzheimers Disease: More than Just a Plaque

Scientific comparative study of Alzheimers disease and its association to amyloid beta-protein

By Kelly Jennings, ND

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Soscia SJ, Kirby JE, Washicosky KJ, et al. The Alzheimer’s disease-associated amyloid beta-protein is an antimicrobial peptide. PLoS One. 2010;5(3):e9505.


Basic science comparative study


Comparison of human brain tissue from temporal lobe and cerebellum of 32 Alzheimer’s disease (AD) patients and 13 non-demented age-matched control subjects. Human brains were obtained 12–24 hours postmortem. Clinical diagnosis of AD was confirmed by subsequent histological evidence of amyloid plaques and neurofibrillary tangles. Samples of brain tissue were assayed and inoculated with a variety of cell cultures.

Main Outcome Measure

To determine the normal physiologic role of amyloid beta (Aß)-protein and compare antimicrobial activity of AD brain tissue versus normal control brain tissue.


AD is characterized by a loss of neurons and synapses in the cerebral cortex and certain subcortical regions. This loss results in gross atrophy of the affected regions, including degeneration in the temporal lobe and parietal lobe and parts of the frontal cortex and cingulate gyrus. Studies using MRI and PET have documented reductions in the size of specific brain regions in patients as they progressed from mild cognitive impairment to AD and in comparison with similar images from healthy older adults.
The dominant hypothesis regarding the development of AD targets Aß plaques as the primary causative factor in the pathogenesis of the disease. Support for this theory, which was developed in 1991, is based on several genetic findings and imaging studies. Presence of the apolipoprotein E (APOE) genotype is a major risk factor for AD and strongly correlates with an increased accumulation of amyloid buildup in the brain before AD symptoms arise. In these cases, Aβ deposition precedes clinical AD. The location of the gene for the Aß precursor protein (APP) is on chromosome 21, and people with trisomy 21 (Down Syndrome) who have an extra gene copy almost universally exhibit AD by 40 years of age. Genetic studies have shown that mice expressing a mutant form of the human APP gene develop fibrillar amyloid plaques and Alzheimer’s-like brain pathology with spatial learning deficits. Plaques are dense, mostly insoluble deposits of Aß peptide and cellular material outside and around neurons. Tangles are aggregates of the microtubule-associated protein tau that have become hyperphosphorylated and accumulate inside the cells themselves.
Both amyloid plaques and neurofibrillary tangles are clearly visible by microscopy in brains of those afflicted by AD
Both amyloid plaques and neurofibrillary tangles are clearly visible by microscopy in brains of those afflicted by AD.
Although many older individuals develop some plaques and tangles as a consequence of aging, the brains of AD patients have a greater number of them in specific brain regions such as the temporal lobe.
The amyloid hypothesis of AD has come into question in recent years, as clinical progression of AD seems to show poor correlation with the amount and progression of amyloid plaque formation shown on imaging studies. Clinical trials using antibodies against Aβ protein have, to date, shown little success clinically, suggesting that Aβ protein is perhaps not the main causal agent in AD. An experimental vaccine found to clear the amyloid plaques in early human trials did not have any significant effect on Alzheimer’s-related dementia.
Consequently, AD research has been exploring other theories and plausible etiologies of the disease.

Key Findings

Aß protein, isolated from the brain tissue of people with AD, has potent antimicrobial activity against 8 common clinically relevant microorganisms, including Candida albicans and gram+ and gram– bacteria. Brain samples from Alzheimer’s patients were 24 percent more active in killing Candida albicans as compared to brain tissue from normal controls. This effect was canceled if the AD brain tissue was first treated with antibodies to Aβ.

Practice Implications

Amyloid β proteins have traditionally been characterized as insoluble fibrous protein, catabolic byproducts of protein folding with little to no normal physiologic function. The primary author of this study, however, noted that the genes that code for innate immunity are remarkably similar to those genes implicated in AD. This led to an interesting hypothesis. Could it be that, contrary to Aβ proteins acting as the primary cause of AD progression, the presence of Aβ proteins may actually signify something different: the activation of innate immunity in the brain?
To test this theory, researchers needed to better characterize the function of Aβ proteins. What this article determined is that Aβ protein is a specific ligand for a number of different receptors, is transported by complex trafficking pathways, and has a potent antimicrobial effect in the brain.
These findings may make us reevaluate some assumptions about AD. I have previously written about other research that proposes a breakdown of the integrity of the blood brain barrier (BBB) as a possible factor involved in the etiology of Alzheimer’s. What if it is this breakdown that signals the beginning of a cascade of events leading to the development of Aβ plaques and neurofibrillary tangles, which are in actuality just the end products of an adaptive process? If so, certain observations should fit with this theory. In the spirit of hypothesizing, let’s try this: Oxidative stress, mini-vascular events, and other factors as yet undetermined lead to a breakdown in the BBB (we can term this “leaky brain”). This breakdown wreaks havoc on concentration gradients that are normally well maintained within the brain. The brain now becomes susceptible to microbial invasion that normally would have been deterred by an intact BBB. These microbes invade the brain, driving chronic activation of the innate immune response, creating inflammation and neuronal damage. Intracellular trafficking pathways are affected. Aβ protein, a potent antimicrobial peptide, is activated as past of this response. These proteins form plaques, which we can observe on imaging studies.
Some supporting evidence:
1) A number of studies have reported that the central nervous systems of AD patients are infected with pathogens including Chlamydia pneumoniae, herpes simplex virus, Borrelia spirochetes, and Helicobacter pylori. , ,
2) APOE4 is involved in neuronal cholesterol transport and is a major genetic risk factor for AD. Defects in APOE can result in familial dysbetalipoproteinemia, or type III hyperlipoproteinemia (HLP III), in which increased plasma cholesterol and triglycerides are the consequence of impaired conversion of very-low-density lipoprotein (VLDL) and intermediate density lipoprotein (IDL) to low-density lipoprotein (LDL) as well as impaired clearance of chylomicron, VLDL, and LDL remnants. Elevated cholesterol can be one of the sequelae of chronic inflammation.
3) Every neuron has a cytoskeleton, an internal support structure partly made up of structures called microtubules. These microtubules act like tracks, guiding nutrients and molecules from the body of the cell to the ends of the axon and back. The tau protein stabilizes the microtubules when phosphorylated. In AD, tau undergoes chemical changes, becoming hyperphosphorylated; it then begins to pair with other threads, creating neurofibrillary tangles and disintegrating the neuron’s transport system. This could also be a result of chronic inflammation and neuronal damage.
With the recognition that there is some basic science and mechanistic explanation missing in this story—with many gaps implied—it is worthwhile to note is that there seems to be a move to understanding the adaptive role of Aβ proteins. The finding that Aβ proteins are antimicrobial and involved in the innate immune response could turn the discussion of AD on its head and allow researchers to continue to seek a deeper cause for what is going on in AD. Aβ plaque formation may be the result of an adaptive physiology gone overboard—the brain trying to protect itself from microbial invasion and consequent neuronal damage. Inflammation and oxidative stress certainly play roles here, and as such proper nutrition, anti-inflammatory protocols, and digestive health, hallmarks of naturopathic therapeutics in the prevention of Alzheimer’s, would certainly be well supported.

About the Author

Kelly Jennings, ND, is a board certified naturopathic physician and licensed acupuncturist. She graduated valedictorian of her class at the National College of Natural Medicine in 2007. She also has a B.A. with Honors in Neuroscience from Amherst College in Massachusetts and was clinical research associate at Memorial Sloan Kettering Cancer Center in New York City prior to medical school. She is co-author of The Breast Cancer Companion, has been published in several medical journals and is writing a seasonal dietary therapy manual for patients. She is currently in practice at Urban Wellness Group in Portland, Oregon.


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