Alzheimer’s disease (AD) is a progressive and irreversible neurodegenerative disorder affecting over 35 million people worldwide. As the global population ages, AD is projected to reach epidemic proportions. Whilst health care systems worldwide need to act to address this growing economic and social burden, scientific research is under pressure to reach a better understanding of the mechanisms underlying this neurodegenerative disease. At present, the major advances in our understanding of the causes and mechanisms of AD have been achieved by research into molecular biology and protein folding. This article addresses the role of the stress caused in a particular cell organelle, the endoplasmic reticulum (ER), in AD brain cells, and its potential as a therapeutic target.
Alzheimer’s disease (AD) is an age-dependent, irreversible neurodegenerative disorder and the most common form of dementia worldwide. In 2010, it is reported that over 35 million people were living with dementia, 2/3 of who were from developing countries. If the incidence of AD continues to rise at the current rate, it is estimated that as many as 115 million individuals will be affected by the disease by 20501.
While the brain in healthy ageing individuals may shrink to some extent, it does not lose neuronal brain cells in large numbers. Conversely, patients with AD exhibit significant reduction in brain volume resulting from widespread neuronal degeneration. Initial damage occurs in neurons and neural connections in specific parts of the brain involved in memory. Early symptoms of AD are often ignored for some time because they resemble natural signs of ageing. However, as the disease progresses, the damage extends to areas involved in reasoning, language and behavior, leading to a series of consequences including loss of memory, impairment of intellectual ability and changes in behaviour and personality. Eventually, large-scale neural destruction renders the AD patient unresponsive to the outside world.
While the brain in healthy ageing individuals may shrink to some extent, it does not lose neuronal brain cells in large numbers. Conversely, patients with AD exhibit significant reduction in brain volume resulting from widespread neuronal degeneration
A Tangled Case
AD is characterised by the accumulation and formation of abnormal structures in the brain known as amyloid plaques and neurofibrillary tangles. The disease can be classified into different subtypes, based on the age of the onset and the genetic predisposition. Sporadic or late onset AD (LOAD) is the most common form, while familial AD (FAD) is an inherited form of early onset AD that accounts for around 5% of cases.
Recent scientific and clinical research has revealed a genetic basis underlying AD pathophysiology. It is thought the mutations in certain genes could play a role in the breakdown of amyloid precursor protein (APP), a transmembrane protein whose precise function is not yet known. This breakdown is part of a process that generates of toxic species named amyloid-beta (Aβ40 and Aβ42), which precede amyloid plaque formation, a hallmark of the disease2.
At present, there is no cure for AD. Cholinesterase inhibitor compounds, the most effective treatments available, can delay the neurodegenerative process by 6-18 months. Other drugs, such as Aricept® , Exelon® and Razadyne®, aim to alleviate behavioural symptoms such as agitation, anxiety and depression, making the patients feel more comfortable and thus easing their care3. The challenge, therefore, is the discovery of novel molecular targets that could aid the development of new therapies to stop or even prevent AD altogether.
ER Protein Machinery – Under Stress Conditions
The Endoplasmic Reticulum (ER) is the cellular compartment where proteins are synthesised. The newly synthesised proteins are not functional until they obtain their correct 3D structure in a process called protein folding. This process makes the ER a unique compartment with a crucial role in the proper functioning of the cell.
At present, there is no cure for AD. Cholinesterase inhibitor compounds, the most effective treatments available, can delay the neurodegenerative process by 6-18 months
The ER environment can be perturbed by pathophysiological processes such as environmental factors and mutant protein expression, but also from natural processes such as the increased biosynthetic load taking place in the ER. This results in the accumulation of immature (unfolded) and abnormal (misfolded) proteins in the cells causing ER stress. Our body counteracts ER stress with an adaptive response called the ‘Unfolded Protein Response’ (UPR), which activates signalling cascades that elicit changes in metabolism and gene expression required to manage the stress situation. As long as the UPR can reduce ER stress, our body works correctly. However, when the level of stress induced by the accumulation of misfolded proteins cannot be controlled by the UPR, ER stress, which initially acts as a proactive mechanism for the cells, has the capability to induce an inflammatory response and programmed cell death (apoptosis).
Managing ER Stress in AD
ER stress has been proposed as a potential mechanism for age-related decline in general tissue mass and function and, in particular, in neurodegeneration. Research has shown that there is age-related decline in the ability of the ER to overcome stress, mostly through inactivation or decreased synthesis of critical molecular chaperone proteins such as BiP, involved in facilitating the 3D assembly of newly synthesized proteins. Chaperones sense the level of unfolded proteins in the ER and act as ER stress sensors.
The ER is extremely sensitive to disturbances in cellular homeostasis, therefore it is not surprising that many studies investigating protein misfolding diseases such as Alzheimer’s and Parkinson’s, have implicated ER stress as being at least partially responsible for neuronal death. Genetic mutations associated with AD (e.g. mutation in the APP gene) impact ER function and likely reduce its capacity to deal with ER stress, shifting the balance of cellular fate towards the apoptotic pathways rather than recovery. Therefore therapeutic strategies that modulate ER function represent a promising approach for prevention or treatment of AD.
Specific targets for ER regulation have been difficult to find, due to the high degree of cross signalling in the UPR pathway. However, recent research suggests that increasing the ability of the UPR to deal with stress by either upregulating molecular chaperones and/or blocking apoptosis, provide likely treatment avenues for neurodegeneration.
ER stress has been proposed as a potential mechanism for age-related decline in general tissue mass and function and, in particular, in neurodegeneration
One logical strategy is to increase protein-folding capacity by stimulating the over-expression of protein folding chaperones without affecting the activation of other, more detrimental, ER stress events. Related to this is the use of small molecule chaperones to directly affect the solubility and/or folding of the accumulated proteins. Both of these strategies appear promising. A body of evidence from the field of psychiatry suggests that certain mood-altering drugs used in the treatment of diseases, such as bipolar disorder, are able to selectively increase the levels of the chaperone named BiP without triggering ER stress. These include lithium, valproate, and possibly very high (supratherapeutic) doses of carbamazepine. The neuroprotective effects of valproate (such as reduced neuronal cell death and increased cell survival) appear to be particularly noticeable in the frontal cortex, an area affected by AD, and the CA1 region of the hippocampus5. Thus, there has been an increased interest in the potential to provide mood stabilizers drugs to treat neurodegenerative disorders.
Another strategy for new therapeutics that target ER stress involves targeting the cellular control points that determine the point that irreversibly initiates apoptosis (cell death). Drug development and clinical studies on neurodegenerative diseases need to focus on promoting the survival mechanisms and inhibiting the pro-apoptotic pathways. Essentially, it would be useful to develop therapeutics that would modulate the same signalling pathway, but with opposite effects to treat different diseases2.
With the rising prevalence of AD, the urgency to develop new treatments is increasing. Current insights into the importance of ER stress and the apoptotic molecular cascade in the progression of neurodegenerative diseases supports further research to investigate this as a prominent target for drug discovery. It is hoped that this will lead to the development of novel AD therapies that go beyond alleviating the symptoms, and to a new generation of drugs that aim to cure or even prevent this devastating disease.
