Amyloid-beta has long been recognized as the most prominent molecular feature of Alzheimer’s disease, along with tau tangles. In this paper, we explore Alzheimer’s disease through the light of beta-amyloid. We discuss the history of amyloid-beta and its role in Alzheimer’s disease. In addition, we explore its properties, exactly what makes it so toxic, and the evidence that verifies its role in Alzheimer’s disease. Furthermore, we explore the relationship between Amyloid Beta, Alzheimer’s, and the lipid membrane. Finally, we discuss possible avenues of treatment and current areas of research.
What is Alzheimer’s disease?
Alzheimer’s disease is a neurodegenerative disease in which brain cells that process, store and retrieve information degenerate and die. It causes progressive memory impairment and loss of cognitive function. Symptoms include mental confusion, forgetfulness, loss of basic cognitive abilities, and on a more molecular level, aggregates of amyloid-beta protein plaques and tau tangles on blood vessels and neurons . Scientists believe that the oligomers cause amyloid toxicity and are working on preventing it. Other goals include creating more accurate models to study the molecular changes amyloid-beta and potential treatments cause. As of right now, there is no cure or prevention for Alzheimer’s disease.
What is beta-amyloid?
Amyloid-Beta oligomers are the most prominent aspect of the molecular pathology of AD. It is part of a larger protein known as an amyloid precursor protein that extends from the inside of the brain cells to the external environment. Later, it is cut into separate pieces when activated – in some situations, beta-amyloid is produced.
In Alzheimer’s, beta-amyloid gathers around synapses, disrupting communication between neurons, leading to their death. The oligomers are more toxic if they are small and soluble. The amyloid hypothesis assumes that problems in production, accumulation or disposal of this protein lead to the symptoms. The mechanism behind the toxicity of these oligomers is believed to be destabilization of homeostasis through the formation of new ion channels in lipid bilayers. Scientists still don’t know the exact mechanism behind these changes, which could help develop new treatments.
What is the evidence for beta-amyloid relation to Alzheimer’s?
Scientists have been able to prove that beta-amyloid is directly linked to Alzheimer’s. Looking at families across the globe, scientists have been able to pinpoint certain genes that nearly always guarantee the development of Alzheimer’s disease. These mutations are all associated with beta-amyloid production. Furthermore, in experiments with genetically engineered mice, scientists found that mutations in only the beta-amyloid gene lead to Alzheimer’s symptoms. In addition, those with down syndrome who have three copies of the APP gene almost invariably develop Alzheimer’s disease.
What properties of beta-amyloid make it so toxic?
One of the biggest reasons that beta-amyloid causes such problems is that it is chemically stickier than other fragments produced when APP is broken. The protein clumps into clusters known as oligomers. As the disease progresses, the oligomers link together becoming fibrils. Fibrils join together to form beta-sheets, which can join together to form plaques. The plaques are most prominently seen in pictures and contain clumps of various systems.
What is the relation between Amyloid Beta, Alzheimer’s and Lipid Membranes?
Not only does beta-amyloid on its own play a significant role in Alzheimer’s disease, but changes in the lipid membrane also play a part. There are changes in the phospholipid bilayer to sphingomyelin and gangliosides. Sphingomyelin has been consistently shown to decrease in Alzheimer’s disease. Gangliosides, however, have conflicting results. Some studies show that it increases and others say it decreases; similarly, studies are conflicted on whether or not it decreases or increases the probability of plaques and tangles forming. Although some lipids have produced conflicting results, on the whole researchers have found the lipid concentrations and Alzheimer’s (specifically damage to neuronal membranes) are linked and can be used as an indicator.
These changes in the lipid composition of neuronal membranes affect properties such as membrane fluidity, permeability, and domains. These all affect the way amyloid binds in the brain and therefore, the course of Alzheimer’s disease. At the time, there are no models in the literature that can accurately reflect healthy and AD membranes. In order to study the changes that happen to the lipid membranes and their effects on AD, scientists have, in the past, a simple lipid model. Often times the results from such studies can not be directly related to the human body or actual animal subjects as they don’t represent the cell accurately enough. Scientists have begun to choose to pick aspects of the membrane and feature them prominently in the model in order to create a more representative model. Some areas of focus are DPPC, POPC, sphingomyelin, cholesterol, and ganglioside GM1.  In this way, the resulting experiment’s results could be used to mimic healthy and diseased states of real neurons.
To explore the specific changes in the neuronal model with the new model, researcher Elizabeth Drolle designed an experiment. There were three experimental groups: normal, decreased GM1, decreased GM1 and SM. These specific lipid changes were picked because they were observed in vivo most often. Drolle measured the morphology and electrical surface potential of the neurons using BLM, POPC, and AFM. The results showed that the changes in lipid membrane content changed the membrane permeability – throwing the neuron out of homeostasis. Since ion concentration is essential neuronal signaling, these membrane changes caused damage to normal cell function. Particularly in AD cells, these changes also allow Amyloid Beta to penetrate further into the cell, further increasing its toxicity. This discovery opens up a new avenue for treatment research.
In addition to these changes, Drolle’s results lead her to a new hypothesis regarding amyloid’s toxicity. This theory postulates that amyloid has protective roles in the brain to fight against the bacteria and microbes without affecting the host cell. AMP’s such as amyloids are able to recognize bacterial membranes using electrostatic interactions. These changes in the neuronal membranes prevent amyloid-beta from performing its normal function and cause amyloid-beta plaques to build up. If we were able to prevent this, we could prevent mass cell death.
What are the potential avenues of treatment?
Scientists have been looking for a treatment for Alzheimer’s disease for decades, However, until the drug known as aducanumab, there was no large-scale successful therapy discovered. It was the first drug that was shown to have a positive effect in studies on Alzheimer’s disease by binding to beta-amyloid and reducing the rate of cognitive decline. The drug is currently in clinical trials but it opened up new avenues for scientists to study treatments. Some directions are outlined below:
Current research aims to change the behavior of the enzymes and proteins that break Amyloid Precursor Protein into smaller fragments. These proteins are known as secretases, with beta and gamma secretases being the most prominent. Scientists are either trying to change the interactions the enzymes have with APP (i.e. to create fragments other than APP) or create drugs that block the secretases.
Scientists are also exploring drugs that can prevent the formation of the fibrils, mats, and plaques discussed above as some studies indicate that the toxic effects of beta-amyloid begin before the separate molecules begin to interact. Some methods include “mobilizing the immune system to produce antibodies to attack beta-amyloid, administering laboratory-produced antibodies to beta-amyloid and administering natural agents with anti-amyloid effects.”
There are two types of antibodies being studied – active and passive vaccines. Active vaccines have a virus or protein that has beta-amyloid attached. Theoretically, this should prompt the body to produce antibodies in response and reduce levels of beta-amyloid in the brain. Passive vaccines, on the other hand, are predetermined doses of antibodies that can be produced in the laboratory. In this way, the vaccine doesn’t rely on the body to produce antibodies but directly supplies them. In addition, some researchers are looking into natural agents with anti-amyloid properties such as IVIg, intravenous immunoglobulin in the plasma of human donors. It has been shown to contain natural antibodies that could reduce beta-amyloid levels.