ReviewAscending monoaminergic systems alterations in Alzheimer's disease. Translating basic science into clinical care
Graphical abstract
Introduction
Even with the recent slowdown in the economy, the past three decades have witnessed an incredible rate of economic growth around the world. For instance, China, India, and Brazil (comprising around 40% of the world population) have increased their average gross domestic product by 10-fold. The sustained economic prosperity in these countries has been closely linked to an increase in life expectancy. As a result, the world population is becoming increasingly old. In case of China, the number of individuals 60 years and older has increased from 76 million in 1982 to more than 130 million in 2006 (Flaherty et al., 2007).
Dementia, primarily caused by Alzheimer's disease (AD), is one of the most important health challenges linked to aging (Savva et al., 2009). In 2001, a report by AD International estimated that there were 24.3 million cases of dementia worldwide, of which, 60% reside in developing countries (Prince et al., 2004). Currently, there are 5.4 million people with AD in the US and this figure is expected to reach 16 million by 2050. In addition to the incredible human toll (Minino, 2011), AD has also been proven to be economically expensive. The cost of providing care for AD patients has been shown to be three times higher than other disorders affecting people 65 years and older (Thies and Bleiler, 2011). In 2010, the annual economic cost of dementia in the world was estimated to be around US$ 604 billion (Wimo and Prince, 2010).
AD is a neurodegenerative disorder leading to both macroscopic and microscopic structural alterations and dysfunction of multiple neuronal circuits in the brain. Macroscopically, AD is associated with brain atrophy particularly in the hippocampus and cortical regions along with widening of lateral ventricles (Kim et al., 2012). At the microscopic level, AD has been linked to senile plaques, neurofibrillary tangles (NFT), as well as synaptic and neuronal loss particularly in the hippocampus and temporal cortex. Senile plaques are characterized by dystrophic neurites containing abnormal mitochondria, lysosomes, and microtubules in the periphery and amyloid β (Aβ) in the core region. Neurofibrillary alterations (i.e. NFTs, dysmorphic neurites surrounding Aβ, and neuropil threads) are mostly intracellular accumulations of paired helical filaments. Among cortical regions, the entorhinal cortex (EC) has been shown to be the first region to display AD changes while primary sensorimotor areas are generally spared (Braak et al., 1993).
In addition to the occurrence of plaques and tangles in the cortex, AD is associated with degeneration of subcortical populations, particularly cholinergic and monoaminergic (MA-ergic) systems (Wenk, 2003). The affected neurons are generally characterized by long and poorly myelinated axons, extensively projecting to hippocampal and cortical regions. Through vast innervation, these numerically sparse subcortical regions impose a strong modulatory influence on hippocampal and cortical cells. Neuroanatomical studies in animal models of neurodegeneration have indicated that all these regions play significant roles in attention and memory acquisition and retrieval. A question has been raised regarding the role of degeneration of these subcortical regions in the pathophysiology of AD. We have previously reviewed the role of degeneration of the cholinergic system in AD (Salehi et al., 2007b). Here, we aim to review the status of MA-ergic systems in the brainstem and hypothalamus and their ascending projections in the pathophysiology of AD. In AD, as in Down syndrome (DS), there is a degeneration of ascending cholinergic fibers arising from basal forebrain cholinergic neurons. In our previous studies, we were able to link the loss of cholinergic neurons in the Ts65Dn mouse model of DS to a defect in the retrograde transport of nerve growth factor (NGF) associated with abnormal early endosomes. Interestingly, failed NGF axonal transport in Ts65Dn mice was linked to the over-expression of amyloid precursor protein (App) in these mice (Salehi et al., 2007b, Millan Sanchez et al., 2011). We also found similar relationship between App over-expression and degeneration of MA-ergic neurons in the locus coeruleus (LC) in the Ts65Dn mouse model of DS (Salehi et al., 2009a).
It has been known for long that MA-ergic systems are widely affected in AD. Mann and colleagues reported significant reduction in the nucleolar volume and total RNA levels in both serotonergic (5-HT-ergic) and norepinephrinergic (NE-ergic) neurons in the brainstem of AD patients (Mann et al., 1982, Mann et al., 1984). Several new studies including our own, confirmed MA-ergic neuron degeration (Himeno et al., 2011, Jurgensen et al., 2011, Kalinin et al., 2011, Salehi et al., 2009a) and have successfully targeted these systems for the treatment of cognitive dysfunction in mouse models of neurodegeneration. In light of these new findings – as well as of reports that polymorphisms in MA-ergic related genes are associated to behavioral and cognitive features of AD (Borroni et al., 2004, Witte and Floel, 2012) – it has become necessary to revisit the current status of knowledge about the role of MA-ergic systems in the pathogenesis of AD.
The positive effects of improving NE-ergic system on cognition in mouse models of neurodegeneration (Salehi et al., 2009a) have now been complemented by additional exciting studies indicating that the activation of MA-ergic systems is also able to modulate the severity of AD-related pathology in these mice (Himeno et al., 2011). Recently Li et al. (2013) found that β2ARs play a significant role in modulating the effects of enriched environment in mouse models of AD. The role of MA-ergic system particularly NE-ergic in DS, has recently been examined (Millan Sanchez et al., 2011). We hope that this review will further encourage the use of new techniques in understanding mechanisms behind degeneration of the MA systems in AD and targeting them as a therapeutic strategy in restoring cognitive function, limiting non-cognitive symptoms, and reducing the severity of pathology in affected people.
Donnan (2008) has highlighted the challenges of translating encouraging findings in animal models into clinical interventions. These challenges include quality of animal studies, sub-optimal animal models, lack of complete understanding of the effects of drugs in human tissue, and problems with the design of clinical studies. One such difficulty is the difference between the pathophysiology of human AD (especially sporadic AD) and that of transgenic mice. Transgenic mouse models have been available for more than a decade and have been instrumental in helping us understanding the biology of AD. A majority of these models are based on over-expression of mutant APP. Transgenic mouse models overexpressing APP and presenilin (PS1) develop amyloid deposits, varying degrees of cognitive deficits, and for the most part exhibit no neuronal loss in brain regions affected in AD (McGowan et al., 2006). Although this is congruent with the observation in humans that amyloid plaque burden does not correlate with cognitive impairment (Terry et al., 1991), it also points out that these models do not replicate all important features of human neurodegenerative disorders particularly AD. On the other hand, mouse models that overexpress TAU transgenes exhibit early stage NFT formation; resemble human pathology more closely. Interestingly, structural and functional synaptic abnormalities have been detected in all models, i.e. a feature that correlates best with cognitive decline in AD (Terry et al., 1991).
Section snippets
Chemoarchitecture of the MA-ergic systems and their alterations in AD
The early work by Fuxe, Dahlström, Anden, and others in the 1960's and 1970's allowed the mapping of the MA-ergic pathways arising from the brainstem and projecting to the rest of brain and spinal cord (see Fuxe et al., 2007). These authors identified neurons using dopamine (DA), NE, and serotonin (5-HT) as neurotransmitters with their soma located in the brainstem in A9–A10, A4–A6, and B7–B8 groups respectively (Dahlstrom and Fuxe, 1964) (Fig. 1, Fig. 2, Fig. 3). Later on, histamine (HA)-ergic
Chemoarchitecture
DA is a catecholamine synthesized from L-tyrosine by the sequential action of tyrosine hydroxylase (TH) and aromatic L-aminoacid decarboxylase (AADC). DA is metabolized by DA β-hydroxylase (DBH) into NE, and by monoamine oxidase B (MAO-B) and cathechol-O-methyltranferase (COMT) to homovanillic acid (HVA). The main DA-ergic regions in the midbrain are located in areas A8–A10. While area A8 refers to retrorubral field, A9 and A10 correspond to SN and VTA respectively. The DA-ergic neurons arising
Chemoarchitecture
NE is produced from DA by DBH and is metabolized through various pathways involving MAO-A and COMT, into vanillylmandelic acid (VMA) and 3-methoxy-4-hydroxyphenylglycol (MHPG).
NE-ergic cells in the brain are found in the LC, the periaqueductal grey area (A6), as scattered cells in the nucleus subcoeruleus, the subependymal extension of the LC (A4), the paragigantocellular nucleus (A5), and in the ventral nucleus of the lateral lemniscus (A7). The majority of ascending fibers from the NE-ergic
Chemoarchitecture
5-HT is an indolamine produced from L-tryptophan by the sequential action of tryptophan hydroxilase (TPH) and AAAD and is metabolized by MAO-A into 5-hydroxyindoleacetic acid (5HIAA). Dahlström and Fuxe labeled 5-HT cell groups as B1–B9, including B1–B3 in the medulla, B4–B9 in the pons, and midbrain (B1, raphe pallidus; B2, raphe obscurus; B3, raphe magnus; B4, dorsal to prepositus hypoglossi; B5, raphe pontis; B6, caudal part of raphe dorsalis; B7, raphe dorsalis; B8, centralis; B9, the
Chemoarchitecture
HA is synthesized from L-histidine by histidine decarboxylase (HDC). The enzyme is expressed in the brain, mast cells, stomach, and the liver. HA is metabolized by HA-N-methyl-transferase (HMT), MAO, and aldehyde dehydrogenase. So far, 4 different HA receptors have been identified. While H1-H3 receptors, i.e. members of GPCRs family are mainly found in the brain, H4 receptors are primarily expressed in the immune and hematopoietic systems. H1Rs have been detected in the neocortex, claustrum,
Conclusions
All four principal nuclei of the ascending MA-ergic systems undergo significant degeneration in AD. This, results in alterations in MAs concentrations in regions receiving projections from MA-ergic neurons. The loss of strong modulatory inputs from the MA-ergic systems to the hippocampal and cortical neurons would lead to de-afferentation of these regions in AD (Sanchez et al., 2011). Since AD is indeed a multisystem disorder affecting multiple neuronal populations including cholinergic (Salehi
Acknowledgements
This study was supported by grants from the Down Syndrome Research & Treatment Foundation (DSRTF), Research Down Syndrome (RDS) and the MIRECC and WRIISC programs at the VA Palo Alto Health Care System. We are very grateful to Ms. Persia Salehi for design and production of graphic work used in this study.
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Current address: Department of Psychiatry, School of Medicine, Washington University in St. Louis, MO, USA.