Abstract
In recent years, there has been an advancement in the understanding of the role of amyloid β-protein in the pathogenesis of Alzheimer’s disease. This has resulted in a progression in the areas of diagnosis and treatment. This review article will discuss the lasting impact that the discovery of amyloid β-protein (Aβ) has on AD, present a review of the biological characteristics of AD and the aspects of the modern treatments that are being used. A further look into the disease mechanism behind the amyloid hypothesis will also be researched, along with the brain Aβ in AD.
Contents
1. Introduction
2. The importance of the discovery of amyloid β-protein on the understanding of Alzheimer disease
3. Biochemical characteristics of AD
4. Disease mechanism associated with the amyloid hypothesis
5. Brain amyloid-β oligomers in ageing and Alzheimer’s disease
6. Aspects of treatment
6.1. The role of Vitamin C in the Brain
7. Discussion
1. Introduction
The rapidly increasing prevalence of the aging population has highlighted an important public health concern due to an increase in the number of dementia cases rising through the developed and developing countries. Alzheimer’s disease (AD) is a chronic neurodegenerative disease that is the leading cause of dementia, approximately 60 – 70% of all cases. During normal aging, the brain undergoes a gradual decline in cognitive function. However, in AD there is a rapid cognitive decline. Cognitive function comprises of the processes and skills required to gain knowledge. It is therefore known that the clinical symptoms of AD and in association, dementia, are memory loss and abnormal behaviour such as aggression and depression. The cases of AD are becoming more prevalent as life expectancy increases; this proposes that age is a main risk factor.
There are several proposed hypotheses that can result in AD but it is widely regarded that the ‘amyloid hypothesis’ is the defining feature. It suggests that the abnormal production of the amyloid β-protein (Aβ) in the areas of the brain serving memory and cognitive functions are the cause of AD. This postulate can be supported by looking further into the location of the gene for the amyloid precursor protein (APP) on chromosome 21, along with the fact that individuals with trisomy 21 (Down syndrome) who have an extra gene copy always show signs of dementia by the age of 40 (Nistor, et al., 2007).
Since the brain is made of tissue that have a low regeneration capability, it is of the highest importance to diagnose AD at an early stage so that an interference with any irreversible neurological changes can occur. One of the main issues concerning with AD is that there is a lack of a widely accepted and early laboratory diagnosis to support neuropsychological evaluation, monitor disease development and spot early signs of any affected individuals (Parnetti & Chiasserini, 2011). There has been research to see if the process of Aβ misfolding and oligomerization begins years before any onset of clinical indications and there has been several findings that are conclusive (Peder Buchhave, et al., 2012) In addition to the build-up of the toxic Aβ aggregates, AD has also been discovered to cause oxidative stress and mitochondrial dysfunction (Peizhong Mao & Reddy, 2011)
2. The importance of the discovery of amyloid β-protein on the understanding of Alzheimer disease
It was only when researching into the history of the amyloid β-protein (Aβ) that a related article was discovered which presented the importance of Aβ in the fundamental mechanism of Alzheimer’s disease (Masters & Selkoe, 2012). The authors of this journal article discovered that it was the isolation and partial sequencing of the meningovasular Aβ by George Glenner and Caine Wong in 1984 which proved to be the biggest advancement in the understanding of AD.
3. Biochemical characteristics of AD in relation to amyloid β
When it comes to comparing neurological diseases, Alzheimer’s is known to rank high in relation to the complexity and pathophysiology of different neurological diseases. AD has been identified as a protein folding disease, which is also referred to as proteopathy. A proteopathic disease can be defined as a class of disease in which specific proteins become structurally abnormal and become toxic. This leads to the disruption of functionality in the neuronal cells and ultimately, cell death (Walker & LeVine, 2000). The main hallmark of AD are the amyloid deposits found on the brain. These deposits consist of amyloid β-proteins and neurofibrillary tangles (NFTs) (Lewczuk, Mroczko, Fagan, & Kornhuber, 2016).
Amyloid β also form fibrils that are associated with the plaques that cause AD. These specific fibrils have biochemical characteristics that are worth researching. In vitro studies into the structure of Aβ fibrils have been carried out to show that they are very polymorphic and that they have molecular structures that depend on aggregation conditions. These studies were carried out using solid-state nuclear magnetic resonance (NMR), electron microscopy and other techniques. From the data found from all these studies, structural models were detailed from the fibrils in vitro and they show that the polymorphs of amyloid fibrils can differ in specific aspects. These aspects included the overall structural symmetry and peptide conformation of the fibrils, and also the interresidue interactions within (Lu, et al., 2013).
4. Disease mechanism associated with the amyloid hypothesis
It is not entirely known as to how the production and aggregation of the amyloid β-protein is the main feature of Alzheimer’s disease pathology. However, research into the pathology of AD in 1992 has led to the creation of the amyloid cascade hypothesis. It suggests that the deposition of amyloid β-proteins (Aβ) is the initial pathological incident in AD leading to amyloid plaques and then to neurofibrillary tangles (NFTs), neuronal death and eventually dementia (Reitz, 2012).
There are two key explanations in the original formulation of the amyloid hypothesis. Firstly, the detection of Aβ as a main factor to the production of the plaques and secondly, mutations of the amyloid precursor protein (APP) (Goate, Chartier-Harlin, & Mullan, 1991), the PSEN1 and PSEN 2 genes (Sherrington, Rogaev, & Liang, 1995) which were discovered in family histories with an early onset of AD (disease onset < 60 years). As a result, the production of the amyloid plaques in association with these mutations was observed to lead to neuronal dysfunction and death which is then related to the clinical symptoms of dementia.
There is no consensus as yet to whether the amyloid hypothesis acts as a Loss- (LOF) or a gain-of-function (GOF) mechanism. (Broeck, Broeckhoven, & Kumar-Singh, 2007)