engleski

Serotonergic system in Alzheimer's disease

The neurobiological background of Alzheimer's disease (AD) includes the accumulation of amyloid plaques and neurofibrillary tangles in the brain (1). The dysfunction in the cholinergic system and the alterations in the other neurotransmitter systems, especially serotonergic and dopaminergic, are thought to be responsible for the cognitive deficits and the behavioral disturbances observed in patients with AD (2). Serotonin (5- hydroxytryptamine, 5-HT) has an important role in the regulation of the synaptic function, neurite outgrowth, synaptogenesis and cell survival. It regulates different physiological functions, behaviors and mood (3). Serotonergic neurons innervate specific brain regions that are important in the regulation of memory and learning processes. The role of 5-HT in AD was investigated mostly using post mortem analysis of the brain tissue, functional imaging techniques and peripheral platelet 5-HT markers. Post mortem studies have found the decrease in the brain concentration of 5-HT and its metabolites and the loss of serotonergic (5-HT-1A, 5-HT-2) receptors in AD (4). Recent PET study suggests that the reduction of 5-HT-1A receptors in hippocampus precede clinical symptoms of AD and could be a potentially sensitive tool for early diagnosis. Blood platelets have been proposed as an easy obtainable, peripheral model for some processes in the presynaptic (5-HT reuptake, 3H- paroxetine binding, monoamine oxidase /MAO/ activity) and postsynaptic (5-HT-2A receptors) parts of the central serotonergic neurons (5). Our recent studies showed that platelet MAO activity might be used as a biomarker for the presence of psychotic features in AD (6) and for the early or late onset AD (7). The reason for the altered platelet MAO activity in AD patients may be related to transcriptional factors(s) that act on transcriptional regulation of the amount of enzyme and/or in the kinetic regulation of the molecular activity of MAO. We have also found a significant relationship between the severity of dementia in AD (assessed by Mini Mental Status Examination /MMSE/) and platelet biochemical markers. A positive correlation was found between MMSE scores and both platelet 5-HT concentration and platelet MAO activity in female patients in the early, middle and late phase of AD. The results indicated that more severe AD symptoms are associated with reduced platelet 5-HT concentration and lower MAO activity. The reasons leading to the alterations of central and platelet 5-HT in AD are still unknown. The reduced 5-HT concentrations in brain, CSF and platelets in AD suggest the decrease in 5- HT synthesis. The main factors that influence 5-HT synthesis are plasma availability of its precursor tryptophan and the activity of the rate-limiting enzyme tryptophan hydroxylase (TPH). Since tryptophan is an essential amino acid, its plasma levels depend on the dietary intake and eating pattern that might occasionally be altered in AD. Low plasma and CSF tryptophan concentration, found in AD, might be a consequence of the enhanced tryptophan degradation via the kynuramine pathway, since a dysregulation of both serotonergic and kynuramine pathways of tryptophan metabolism have been associated with pathophysiology of AD. In addition, the decline in the cognitive performance was observed after tryptophan depletion in healthy volunteers and patients with mild to moderate AD, confirming the role of 5-HT system in behavioral and cognitive changes in AD. Reduced TPH activity was found in some brain areas of patients with AD that might be associated with alteration in 5-HT synthesis. The lack of the cofactors tetrahydrobiopterin and folic acid in AD patients could influence TPH activity and consequently decrease 5-HT synthesis. As a cofactor for nitric oxide synthase, tetrahydrobiopterin is also involved in the production of free radicals within the cell that could impair 5-HT synthesis through oxidative damage of TPH. The polymorphisms in 5- HT-related genes may be interesting candidates for neuropsychiatric manifestations of AD. Several studies indicated the positive association between T102C polymorphism of the 5- HT-2A receptors gene and behavioral and psychological symptoms of AD (8). In addition the insertion/deletion polymorphism in the promoter region of the 5-HT transporter gene (5-HTTLPR) may predispose patients with AD to develop aggressive behavior. In conclusion, the results of the current investigations confirm the role of 5-HT system in pathogenesis of AD, particularly in behavioral and cognitive symptoms of AD. References: 1. Forsyth E, Ritzline PD. An overview of the etiology, diagnosis and treatment of Alzheimer disease. Phys Ther 1998 ; 78: 1325-31. 2. Garcia-Alloza M, Gil- Bea FJ, Diez- Ariza M, Chen CPL, Francis PT, Lasheras B, Ramirez MJ.. Cholinergic-serotonergic imbalance contributes to cognitive and behavioural symptoms in Alzheimer’ s disease. Neuropsychologia 2005 ; 43: 442-9. 3. Lucki I. The spectrum of behaviors influenced by serotonin. Biol Psychiatry 1998 ; 44: 151-62. 4. Salmon E A review of the literature on neuroimaging of serotonergic function in Alzheimer’ s disease and related disorders. J Neural Transm 2007 ; 114:1179-85. 5. Camacho A, Dimsdale JE. Platelets and psychiatry: lessons learned from old and new studies. Psychosom Med 2000 ; 62: 326-36. 6. Mimica N, Muck-Šeler D, Pivac N, Mustapić M, Deželjin M, Stipčević T, Presečki P, Radonić E, Folnegović- Šmalc V. Platelet serotonin and monoamine oxidase in Alzheimer's disease with psychotic features. Coll Antropol 2008 ; 32 (Suppl 1): 119-22. 7. Mimica N, Muck-Seler D, Pivac N, Mustapić M, Folnegović-Šmalc V. Platelet serotonin and monoamine oxidase activity in patients with early- onset and late-onset of Alzheimer's disease. Period Biol 2005 ; 107: 211-15. 8. Pritchard AL, Harris J, Pritchard CW, Coates J, Haque S, Holder R, Bentham P, Lendon CL. Role of 5- HT2A and 5-HT2C polymorphisms n behavioural and psychological symptoms of Alzheimer’ s disease. Neurobiol of Aging 2008 ; 29:341-47.

Serotonin; Alzheimer' disease

nije evidentirano