The serotonergic system in ageing and Alzheimer's disease

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Abstract

Alzheimer's disease (AD) is one of the major neurodegenerative diseases that deteriorates cognitive functions and primarily affects associated brain regions involved in learning and memory, such as the neocortex and the hippocampus. Following the discovery and establishment of its role as a neurotransmitter, serotonin (5-HT), was found to be involved in a multitude of neurophysiological processes including mnesic function, through its dedicated pathways and interaction with cholinergic, glutamatergic, GABAergic and dopaminergic transmission systems. Abnormal 5-HT neurotransmission contributes to the deterioration of cognitive processes in ageing, AD and other neuropathologies, including schizophrenia, stress, mood disorders and depression. Numerous studies have confirmed the pathophysiological role of the 5-HT system in AD and that several drugs enhancing 5-HT neurotransmission are effective in treating the AD-related cognitive and behavioural deficits. Here we present a comprehensive overview of the role of serotonergic neurotransmission in brain development, maturation and ageing, discuss its role in higher brain function and provide an in depth account of pathological modifications of serotonergic transmission in neurological diseases and AD.

Highlights

► Comprehensive overview the role of serotonin from development aging, including Alzheimer's disease (AD). ► In depth analysis of serotonergic neurons, projections, receptors, and their physiological and pathophysiological roles. ► Serotonergic neurotransmission plays an important role in memory, both directly and via other transmitter systems modulation. ► Dysfunctional serotonergic system is implicated in the pathophysiology of ageing and AD. ► Deficits in serotonergic neurotransmission directly correlate with AD memory impairments, which can be reversed by serotonomimetic drug treatments.

Introduction

An increase in life expectancy coincides with an increased risk of dementia at an advanced age. Over 35 million people worldwide are affected by dementia (Cumming and Brodtmann, 2010), with Alzheimer's disease (AD) being one of the most common causes in the elderly population (Qiu et al., 2009). Initially described by Alois Alzheimer (Alzheimer, 1907) as dementia praecox (and named Alzheimer's disease after him by his colleague and friend Emil Kraepelin several years later (Kraepelin, 1910)). AD is a severe neurodegenerative pathology associated with specific histopathological markers: (i) focal extracellular deposits of fibrillar β-amyloid (also called neuritic or senile plaques) in the parenchyma of the brain and the walls of blood vessels, and (ii) intraneuronal accumulation of neurofibrillary tangles composed of abnormal hyperphosphorylated tau filaments (Braak and Braak, 1991; for review see Duyckaerts et al., 2009).

AD affects specific brain regions associated with learning and memory, notably the basal forebrain, the hippocampus and the neocortex (Takeda et al., 2006, Truchot et al., 2007). Clinical symptoms of AD are manifested by a progressive impairment of cognitive functions including short- and long-term memory (Mohs, 2005). At advanced stages of the disease, AD patients also exhibit behavioural disturbances including agitation, irritability, anxiety, delusions and depression (Lyketsos and Olin, 2002). Epidemiologically, AD is classified into early-onset familial Alzheimer's disease (FAD) and late-onset sporadic AD, or SAD (Blennow et al., 2006). Late-onset SAD accounts for the majority (95%) of AD cases in people above 65 years of age (Kern and Behl, 2009, Shastry and Giblin, 1999). FAD is associated with mutations in three genes coding for amyloid precursor protein (APP), presenilin-1 (PS-1) and presenilin-2 (PS-2), which are inherited in an autosomal dominant mode (Shastry and Giblin, 1999). FAD most commonly occurs in patients between 40 and 65 years of age and is characterised by a rapid progression (Shastry and Giblin, 1999).

The AD-related lesions begin with degeneration of acetylcholine (ACh)-ergic neurones in the nucleus basalis of Meynert and septum followed by accumulation of intraneuronal β amyloid (Aβ), subsequent formation of extracellular neuritic plaques and intracellular neurofibrillary tangles (NFTs), synaptic loss and neuronal death (Mesulam et al., 2004). Synaptic malfunction and synaptic loss occur prior to the development of Aβ-plaques and NFTs; these synaptic alterations are directly associated with deteriorated synaptic strength and synaptic plasticity, including long-term potentiation (LTP) (Scheff et al., 2006, Selkoe, 2002). The neurodegenerative process also involves impaired neurogenesis (Rodríguez and Verkhratsky, 2011a) and multiple reactions of neuroglia from astroglial atrophy and reactive astrogliosis to activation of microglia (Heneka et al., 2010, Rodríguez et al., 2009b, Rodríguez and Verkhratsky, 2011b, Verkhratsky et al., 2010). AD-related neurodegeneration severely affects neurochemistry of the brain. Traditionally, the primary role in AD pathology was assigned to degeneration and demise of ACh neurones and an overall decrease in the activity of choline acetyltransferase (the enzyme responsible for ACh synthesis) (Birks and Melzer, 2000, Bowen et al., 1976, Fibiger, 1991). Other neurotransmitter systems, however, are also involved in cognitive processes and can undergo pathological remodelling in AD; including noradrenalin, dopamine and serotonin, which is the focus of the present review (Dringenberg, 2000, Garcia-Alloza et al., 2005, Grudzien et al., 2007, Lai et al., 2002, Nazarali and Reynolds, 1992). Furthermore, drugs that enhance cholinergic function have only modest success in treating cognitive deficits associated with AD, further alluding to the involvement of other neurotransmitter systems (Birks and Melzer, 2000, Takeda et al., 2006).

Serotonin (5-hydroxytriptamine, 5-HT) plays an acknowledged role in cognition including short- and long-term memory. The raphe nuclei, which contain the majority of 5-HT neurones, give rise to serotonergic projections that are widely distributed throughout the brain notably in areas critical for cognitive functions such as septum, frontal cortex, temporal cortex and the hippocampal formation (Vertes, 1991, Vertes et al., 1999). The effects of 5-HT occur both directly and indirectly through activation of 5-HT-specific receptors and the modulation of other neurotransmission system including cholinergic, glutamatergic, dopaminergic and GABAergic (for review see Buhot, 1997, Buhot et al., 2000, Jeltsch-David et al., 2008, Olvera-Cortes et al., 2008).

Patients with AD-type pathology show decreases in central and peripheral 5-HT neurotransmissions, as revealed by reduced concentrations of 5-HT in the cerebrospinal fluid (Tohgi et al., 1992, Tohgi et al., 1995) and platelets (Mimica et al., 2008, Muck-Seler et al., 2009). Positron emission tomography (PET) and magnetic resonance imaging (MRI) studies have further corroborated an AD-related decrease of 5-HT receptors in the CNS (Kepe et al., 2006, Meltzer et al., 1998a, Meltzer et al., 1999). Post-mortem examination of AD brains revealed decreases in extracellular levels of 5-HT and its metabolite (5-hydroxyindoleacetic acid, 5-HIAA) as well as decreases in expression of 5-HT receptors in various brain regions including the neocortex and the hippocampus (Chen et al., 1996, Garcia-Alloza et al., 2005, Lai et al., 2002, Lorke et al., 2006, Nazarali and Reynolds, 1992, Palmer et al., 1987, Truchot et al., 2008). The impairment of 5-HT neurotransmission in AD is consistent with a loss of 5-HT neurones in the raphe nuclei and associated loss of cortical 5-HT projections (Chen et al., 2000, Yamamoto and Hirano, 1985).

AD-related deficits in 5-HT neurotransmission are associated with accelerated cognitive decline as determined by the Mini-Mental State Examination (MMSE) score (Lai et al., 2002) and with behavioural symptoms including psychosis (Garcia-Alloza et al., 2005) as well as with the severity of dementia. It may therefore, be responsible for the cognitive and non-cognitive abnormalities associated with AD.

Treatments with selective serotonin reuptake inhibitors (SSRIs) increase the CSF concentration of 5-HT and improve cognitive function and memory in patients with dementia of AD type (Marksteiner et al., 2003, Mossello et al., 2008, Mowla et al., 2007, Tohgi et al., 1995). Drugs acting at specific 5-HT receptors have also been suggested as therapeutic agents to enhance cognitive function in AD (Terry et al., 2008).

In this paper we provide a comprehensive overview of the 5-HT neurotransmission pathology in ageing and neurodegeneration with specific emphasis on AD.

Section snippets

Serotonin

Serotonin was discovered as an enterochromaffin substance, which was originally named “enteramine” (Vialli and Erspamer, 1937, Vialli and Erspamer, 1942). Subsequent studies identified 5-HT as a “serum vasoconstrictor” and coined the name serotonin because of its original purification from serum (sero-) and its effect on vessel tone (-tonin) (Rapport, 1949, Rapport et al., 1948a, Rapport et al., 1948b). Some years later, the enteramine-serotonin identity was confirmed, 5-HT was found in the

The serotonergic system in ageing

Age-related alterations of the 5-HT system occur at multiple levels including changes in (i) density of 5-HT-positive neurones in the raphe nuclei, (ii) 5-HT metabolism and hence 5-HT levels in the CNS, (iii) density of 5-HT projections throughout the brain and the spinal cord (iv) expression of 5-HT uptake transporter and (v) expression of 5-HT receptors (see for review Meltzer et al., 1998a, Palmer and DeKosky, 1993).

Serotonergic neurones in AD

Alzheimer's disease is associated with a decreased number of serotonergic neurones in the dorsal and the median raphe nuclei (Table 3) (Aletrino et al., 1992, Chen et al., 2000, Halliday et al., 1992, Kovacs et al., 2003, Yamamoto and Hirano, 1985). Post-mortem studies on AD-affected brains consistently showed a reduced density of 5-HT neurones in the raphe nuclei (Lyness et al., 2003). Abundant Aβ neuritic plaques and neurofibrillary tangles in the dorsal and median raphe nuclei of AD brains

Serotonergic neurotransmission in non-AD dementia

Vascular dementia (VaD) is another common form of dementia (Geldmacher and Whitehouse, 1996). VaD is a consequence of cerebrovascular injury such as stroke and ischemia (Elliott et al., 2009, Kalaria et al., 2004). Epidemiological studies have reported various incidence rates for VaD depending on the geographical location, ranging between 15% and 20% in Europe and Canada to 27–38% in Asia. Similar to AD, there is a higher prevalence of VaD in people with lower levels of education (Di Carlo et

The serotonergic system as a potential therapeutic target in AD

The majority of drugs used for the treatment and management of AD act by reducing the cholinergic deficit (Dringenberg, 2000). However, cholinesterases inhibitors (AChEIs) have limited effects in improving cognitive deficits (for reviews see Clegg et al., 2001, Raina et al., 2008, Takeda et al., 2006).

Several studies have examined the effects of 5-HT drugs on cognitive function in AD (Table 9). Whereas some clinical studies demonstrated significant improvements in cognitive function following

Conclusion

Serotonergic neurotransmission plays an important role in memory, both directly and via modulation of other transmitter systems. A dysfunctional serotonergic system is implicated in the pathophysiology of various mental illnesses including depression, anxiety and schizophrenia. Accumulating evidence emphasises the involvement of the 5-HT system in AD. The link between impaired 5-HT neurotransmission and AD is further supported by imaging studies using PET, SPECT and MRI in living AD patients

Acknowledgements

This work was supported by Alzheimer's Research Trust Programme Grant (ART/PG2004A/1) to JJR and AV. Grant Agency of the Czech Republic (GACR 309/09/1696) to JJR and (GACR 305/08/1381 and GACR 305/08/1384) to AV; the Spanish Government, Plan Nacional de I+D+I 2008-2011 and ISCIII- Subdirección General de Evaluación y Fomento de la investigación (PI10/02738) to JJR and AV and the Government of the Basque Country grant (AE-2010-1-28; AEGV10/16) to JJR. The authors would also like to thank BBSRC

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