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Links of Life

In 2010, 561,666 people died in the UK, of whom 190,721 (34%) were under the age of 75. Of those half a million deaths, just 19,900 (3.5%) were from injuries or poisoning; 161,175 (29%) were from cancer; and 179,078 (32%) were from cardiovascular disease.

It is predicted that about 50% of babies born today will live beyond the age of 80. During their lifetime, these individuals will experience a range of traumatic events and illnesses; and the older they get, the more diseases, statistically, they are likely to suffer. To quote one professor of medicine addressing a cohort of third-year medical students: “If you don’t die of heart disease or cancer, let’s face it, you’ll probably develop dementia” – a sobering thought.

Hidden Disease

Neurodegenerative diseases are a hidden factor when considering life expectancy and causes of death. Concealed behind the cardiovascular and cancer statistics is the fact that Alzheimer’s disease, Parkinson’s disease, other dementias and depression are common sequelae of ageing.

Dementia is a condition characterised by loss of ability to form new memories, progressing to more severe memory loss with inability to recognise friends and family, and then on to difficulties in communication. Dementia is also frequently associated with mood changes. In 2013, some 800,000 individuals were afflicted by dementia in the UK (1.3%). The statistics revealed that approximately 17% of people over 80 years of age were affected, 4% of 70-79 year olds, 1% of 65 to 69 year olds, and less than 0.1% of under 65 year olds (1).

Dementia is not a natural consequence of ageing, and is a disease process that is potentially treatable and preventable – however, it is not a single entity and has multiple causes. Of the 800,000 cases of dementia, Alzheimer’s disease was the most common subtype at 62%, with vascular dementia accounting for 17%. Dementia with Lewy bodies, which is associated with Parkinson’s disease, made up a further 4% of cases (1).

Links with Depression

Major depressive disorder is characterised by persistent low mood with loss of enjoyment (anhedonia); the cardinal symptoms are hopelessness, worthlessness and guilt, with the most extreme outcome being suicide. Around 10% of the population are diagnosed with depression at some point in their lives, although a further 10% typically show the symptoms but do not seek help, are not diagnosed, and do not receive treatment.

Depression is a common symptom of dementia. In a Norwegian study of 1,500 individuals (with a mean age of 72.5 years) referred to memory clinics with suspected dementia or mild cognitive impairment (MCI), 37.5% were assessed as being mildly depressed and 14.1% as being severely depressed – well above population norms.

Shared Aetiology

It is tempting to speculate that the associations between dementia, Parkinson’s disease and major depressive disorder are a consequence of a shared neurodegeneration aetiology.

Alzheimer’s disease is characterised by loss of neuronal tissue in the cerebral cortex and other regions. This loss results in gross atrophy of the affected areas, including degeneration in the temporal lobe and parietal lobe, and parts of the frontal cortex and brain stem – cholinergic neurones appear to be particularly affected. Neuropathologically, the disease is recognised by the deposition of extracellular amyloid-β plaques and intraneuronal neurofibrillary tangles (2).

Amyloid1-40beta-peptide is an endogenous soluble brain peptide which, in Alzheimer’s disease, is transformed to insoluble Amyloid1-42 beta-peptide by mis-cleavage of the trans-membrane amyloid-β precursor protein by β-secretase and γ-secretases. This leads to the formation of the characteristic plaques (3). Neurofibrillary tangles are formed from aggregates of abnormally hyperphosphorylated tau protein. Healthy tau phosphorylates bind to microtubules in the neuron to aid fast axonal transport; hyperphosphorylation of tau alters its conformation in a way that stimulates glycogen synthase kinase 3, disrupting fast neuronal transport (4). The cause for the hyperphosphorylation of tau is still not understood.

Current Treatment

Vascular dementia differs from Alzheimer’s disease in that there is a lack of β-amyloid and neurofibrilliary tangles, although the symptoms of the diseases are essentially similar. Vascular dementia follows a stroke (5), or may be a consequence of prolonged reduced cerebroperfusion – for example, due to atherosclerosis. Therapeutic strategies for vascular dementia and Alzheimer’s disease treatment are largely identical.

The current mainstay for the drug treatment of Alzheimer’s disease and vascular dementia are the anticholinesterase drugs such as donepezil (AriceptTM). The hypothesis underlying their use is that inhibition of acetylcholinesterase results in prevention of the metabolism of the neurotransmitter acetylcholine, thus prolonging its functional life and increasing stimulation of nicotinic and muscarinic cholinergic receptors. Memantine, an antagonist at glutaminergic N-methyl-D-aspartate receptors, has also been shown to be effective against the cognitive symptoms of Alzheimer’s disease, although the mechanism is unclear. None of the current treatments for dementia are targeted at reversing or preventing underlying neurodegeneration. At best, they replace lost neurotransmitters, and are consequently limited in their duration of effectiveness, with growing neurodegeneration.

The treatment of Parkinson’s disease is similar, based on replacing or enhancing lost neurotransmitters. Parkinson’s disease is associated with neurodegeneration of dopaminergic neurones of the substantia nigra. Therefore, treatment is by administration of L-DOPA – a precursor of dopamine able to cross the blood-brain barrier – coupled with inhibitors of the enzyme DOPA decarboxylase, which are not able to cross the blood-brain barrier. This combination prevents the conversion of DOPA to dopamine outside the brain, but enables the conversion inside. Amantadine, which acts by causing release of endogenous dopamine at synapses, can also be used; dopamine receptor agonists such as apomorphine may also be effective. But none of the treatments attempt to limit the neurodegeneration.

Multiple Hypotheses

There are several hypotheses concerning the aetiology of depression and the mechanism of action of antidepressant drugs, the oldest being the ‘monoamine hypothesis’. This hypothesis states that depression is caused by a functional lack of either, or both, of the monoamine neurotransmitters (noradrenaline and serotonin) in the brain, and that antidepressant drugs act by increasing synaptic concentrations of these: monoamine oxidase inhibitors by inhibiting their breakdown; and reuptake inhibitors by preventing their inactivation by reuptake into the presynaptic neurone. Both classes of antidepressants increase the functional longevity of the monoamine transmitters.

This hypothesis, however, is compromised by the following facts: cocaine, a reuptake inhibitor, does not have antidepressant properties; some clinically effective antidepressants appear to be neither monoamine oxidase inhibitors nor reuptake inhibitors; and finally, the neurochemical effects of monoamine oxidase inhibitors and reuptake inhibitors are apparent within hours of administration, but the clinical antidepressant effects take up to two weeks to emerge.

A second aetiology of depression hypothesis centres on the hypothalamicpituitary- adrenal gland (HPA) axis. Depressed individuals typically have elevated plasma cortisol concentrations, possibly indicating an enhanced stress response – but, importantly, their hypothalamus does not display the normal negative feedback response to exogenous cortisol analogue administration. It has been suggested that this abnormal HPA axis function is a consequence of impaired monoamine neurotransmission, and is thus concordant with the monoamine hypothesis.

Currently, the most persuasive hypothesis concerning the aetiology of depression focuses on brain-derived neurotrophic factor (BDNF) (6). The BDNF hypothesis suggests that normal, everyday life events and stress induce neuronal damage which, in healthy individuals, is repaired by the actions of BDNF. In those individuals predisposed to depression, the damage induced by stress accumulates, leading to the psychological features of depression. Antidepressant therapies act by elevating the brain concentrations of BDNF, allowing neuronal repair. This repair process is seen as explaining the two-week delay in appearance of clinical improvement following initiation of antidepressant therapy. Therefore, depression may actually be a neurodegenerative disorder, treated by facilitating neuronal repair.

Decreasing Cardiovascular Actions

The brain renin-angiotensin system (RAS) is an under-recognised neurotransmitter system. The plasma peptide angiotensin II (AII) has long been known to be associated with control of blood pressure, and has been a target for the development of antihypertensive therapies. The biosynthesis of AII begins with the conversion of the large plasma protein angiotensinogen to angiotensin I by the enzyme renin. Inactive angiotensin I is then rapidly converted to the octapeptide AII by angiotensin-converting enzyme (ACE). AII acts via two receptor subtypes: AT1 and AT2. AT2 receptors are present in the foetus and appear to be important in development, but almost disappear in adults, sometimes reappearing at times of wound repair and tissue re-modelling. AT1receptors are responsible for the commonly known actions of AII, namely vasoconstriction and fluid homeostasis. Drugs aimed at decreasing the cardiovascular actions of AII, ACE inhibitors and AII antagonists (AIIA) are now mainstream antihypertensive therapies.

Cognitive and Behavioural Effects

There is a complete, independent RAS in the brain involved with behaviour and cognition (7). Furthermore, a metabolite of AII, angiotensin IV, appears to play a more important role in influencing learning and memory via its own AT4receptor. The binding site for angiotensin IV was initially identified in bovine adrenal cortex and guinea pig hippocampus, and was named the AT4receptor. This was subsequently shown to be identical to the enzyme oxytocinase, which is also named insulin-regulated aminopeptidase (IRAP). Endogenous IRAP cleaves oxytocin, but also has an unrelated action of working in concert with insulin to enhance cellular uptake of glucose. Angiotensin IV both inhibits the aminopeptidase activity of IRAP and enhances insulinmediated glucose uptake.

However, some argue that there is another action of angiotensin IV centred around mimicking hepatocyte growth factor. While the mechanism of action of angiotensin IV is the subject of debate, the fact remains that it can improve learning and memory in animal models. It is also recognised that AII has behavioural effects in animal models: it has been shown to increase anxiety-like behaviour, and reducing its activity has demonstrated a lessening of such behaviour – although rebound anxiety may occur (8,9).

Drugs which inhibit the brain RAS can have antidepressant-like effects in animal models. The potential for the use of ACE inhibitors and AIIA for the treatment of depression has been discussed, and a possible gene polymorphism which enhances AT1 receptor activity has been associated with major depressive disorder (10).

Prevention of Dementia

More recently, is has been recognised that ACE inhibitors and AIIA – when being used for the treatment of hypertension – may have beneficial effects on the symptoms and/ or progression of dementia (11). Experimental evidence demonstrates that the AIIA losartan is able to enhance cognitive performance in healthy young adults (12). The potential of drugs acting on the brain RAS for use in the prevention or treatment of dementia has therefore been proposed, with a currently ongoing clinical trial.

As yet, it is unproven – but now speculated – that clinical use of AIIA and ACE inhibitors may prevent normal metabolism and utilisation of AII – resulting in elevation of the active metabolite angiotensin IV, presumably via other metabolic pathways. Furthermore, it has recently been demonstrated in a preliminary study that angiotensin IV is able to elevate BDNF expression in mouse hippocampus, following prenatal exposure to low-dose ethanol (13). If replicated, the mechanistic pathway of inhibition at AII function leading to elevated angiotensin IV – and therefore elevated BDNF – provides an exciting explanation of the observed involvement of the brain RAS in the treatment of depression, anxiety and dementia. Perhaps BDNF is acting to counteract elements of neurodegeneration, and maybe drugs targeted at the brain RAS could play a role in its prevention or treatment.

But what of Parkinson’s disease? Decreased AT1 receptor binding has been identified in the substantia nigra and striatum of post-mortem brains of Parkinson’s disease patients (14). Treatment with an ACE inhibitor has been shown to elevate dopamine concentrations in mouse striatum and to protect against loss of dopamine neurons (15,16). More recently, using a human neuroglioma H4 cell-line model of Parkinson’s disease, it has been suggested that angiotensin IV may have a protective effect against cell damage (17). Could this be further evidence in support of a potential role for BDNF?

Outside the Brain

Neuronal degeneration in the brain is not the only correlate of ageing. The gastrointestinal (GI) tract has the most elaborate network of extrinsic and intrinsic neurones outside the brain, and only now are these being characterised in relation to ageing. Adding to this complexity, enteric microbiota which have been linked to roles in the development of the intestinal immune system, homeostasis and GI motility (18).

Increasing age is frequently associated with growing incidence of GI disorders such as colorectal cancer, chronic constipation, faecal impaction and faecal incontinence. In fact, it has been shown recently that over 50% of institutionalised elderly suffer from chronic constipation and, from this group, up to 74% use laxatives on a daily basis (19). In the overall population, just 15% of adults suffer from chronic constipation.

To date, not many studies have focused on GI tract ageing, and even fewer have been carried out in humans. However, these few have shown a decrease in colonic transit time with increasing age (20). The rising incidence of these disorders could be associated with neurodegeneration, loss of neuronal and muscle function, or a change in the pathways involved in gut motility. Many studies have investigated changes in neuronal numbers in the intrinsic neuronal network of the GI tract (also known as the enteric nervous system), but results have been highly varied, with some groups reporting elevated neuronal loss of 40-60%, and others showing no significant loss (21,22).

Interestingly, recent research has shown no major neuronal loss in a murine model of ageing (using the C57BL/6 mouse strain), despite an impaired motility phenotype with loss in colonic motility and a significant increase in pellet transit time (21). This research seems to point towards changes in neuronal function or the pathways involved in gut motility, rather than neuronal loss. Further studies have shown that with increasing age, there is a rise in serotonin overflow in mouse colonic tissue, suggesting impaired reuptake, which could also contribute to the phenotype of impaired motility in this model (22).

Neurodegenerative Markers

Despite these findings, markers of neurodegenerative diseases have been found in the GI tract (23). Furthermore, it has been shown that Parkinson’s disease patients often suffer from GI disorders such as constipation. Recent reports have shown that proteinaceous aggregates – characteristic of plaques in neurodegenerative diseases – are found in the GI tract and in the extrinsic nerves connecting the gut to the brain before patients show any symptoms of cognitive impairment (24). These findings are hailing a new era for GI research, focused on identifying early-stage markers for neurodegeneration.

Current treatments for age-related GI disorders centre on alleviating symptoms with stimulant laxatives. However, new therapies are emerging with the use of 5-HT3receptor antagonists, 5-HT4 receptor agonists and guanylate cyclase C agonists (25).

Notably, the RAS system is also present in the GI tract, and AII has been shown to cause colonic contraction (with the release of tachykinins and acetylcholine) via AT1receptors located on enteric neurones (26). In addition, the RAS system has been associated with colorectal cancer, with ACE inhibitors and AIIAs reported to improve metastasis, and a combination of captopril and oral hypoglycaemic agents giving longer survival rates in a mouse model (27).

Future Study

The brain RAS – possibly acting via BDNF – may be useful in preventing or reversing the effects of ageing. Neurotrophic factors, namely BDNF, have displayed a protective role against oxidative stress in neurones (28). Meanwhile, in the gut, researchers have shown that glial cell-line-derived neurotrophic factor (GDNF) can reduce release of reactive oxygen species from myenteric neurones (29). It would be interesting to identify if the RAS system has a similar effect on GDNF in the gut, as it does on BDNF in the brain.

With new therapies emerging to treat neurodegenerative disorders, it is important to look at the overall systemic symptoms – as many cognitive enhancing drugs could have detrimental effects in the GI tract.


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Paul Gard was appointed Professor of Experimental Therapeutics at the University of Brighton in 2013 and is currently acting as Head of the School of Pharmacy & Biomolecular Sciences. He graduated from Nottingham University with a BSc in Psychology and Pharmacology in 1979, and undertook his PhD at the University of Aston, studying the effects of hormones on behaviour. In 1983, Paul joined the staff at Brighton where he has taught pharmacology to students of pharmacy, nursing, podiatry and medicine.

Sara Fidalgo graduated from University of Aveiro in Portugal with a degree in Biology. She worked as a Laboratory Technician at the Gulbenkian Institute for Science before moving to the UK to pursue a PhD in Biochemistry at Imperial College London. In 2010, Sara joined the University of Brighton as a Post-Doctoral Research Fellow in the School of Pharmacy and Biomolecular Sciences, working in the field of pharmacology.

Paul Gard
Sara Fidalgo
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