ReviewLate-life depression and Alzheimer's disease: The glutamatergic system inside of this mirror relationship
Research highlights
► Glutamate and GABA are the principal excitatory and inhibitory CNS neurotransmitters. ► Neurobiology of LLD and dementia is linked to glutamate/GABA system dysfunction. ► The glutamatergic pathway signalling may act as a bridge connecting LLD and dementia. ► Diet could prevent these disorders through the glutamatergic and GABAergic modulation.
Introduction
With a global increase in population size and life expectancy, Alzheimer's disease (AD) has become a world health problem, with 5.3 million of estimated AD cases in the U.S. (Alzheimer's Association, 2010), over 26 million affected worldwide in 2010, and an expected increase to more than 106 million by 2050 (Brookmeyer et al., 2007). Intraneuronal protein clusters composed of extracellular aggregates of β-amyloid (Aβ) [senile plaques (Sp)] and paired helical filaments of hyperphosphorylated tau protein [neurofibrillary tangles (NFT)] are the principal hallmarks of AD pathology, resulting in neuronal synapse dysfunction and compromised cellular integrity (De Strooper, 2010). In adults older than 65 years, another recognized public health problem is late-life depression (LLD), a common and heterogeneous condition that refers to depressive syndromes according to the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV) (American Psychiatric Association, 1994) and the International Classification of Disease-10 (ICD-10) criteria (World Health Organization, 1992). The term LLD encompasses both late-onset and early-onset cases that recur or continue into later years of life (Panza et al., 2010). Various studies present an age range from 45 to 65 years as the lower limit for defining LLD onset (Potter and Steffens, 2007). Estimates of the prevalence of LLD vary widely (from 1.6% to 26.9%) depending on the population studied, sample size, definition of depression, and method of diagnosis (Gottfries, 2001). Among patients with LLD, a subset often develop a reversible form of significant cognitive impairment, commonly called “pseudodementia” or depression with reversible dementia. These patients have a significantly increased risk of developing true dementia at rates as high as 40% over 3 years (Alexopoulos et al., 1993). In addition, a meta-analysis and meta-regression analysis have shown that depression is not only a frequent “prodrome” of AD (Ownby et al., 2006), but a history of depression likely confers an increased risk for later development of AD (Butters et al., 2008). Clearly, depression appears to be closely linked to neurodegenerative processes, and its relationship with cognitive impairment may be bidirectional.
The etiology of late-life depressive disorders is largely unknown, although a causal contribution of genetic, environmental, and social factors is widely acknowledged (Caspi et al., 2003). l-glutamic acid (glutamate, Glu) and γ-aminobutyric acid (GABA) are the principal excitatory and inhibitory neurotransmitters in the central nervous system (CNS), respectively, and increasing evidence suggested that alterations in this neurotransmitter system may contribute to the pathophysiology of depression (Krystal et al., 2002, Cryan and Slattery, 2010). Nonetheless, it remains to be fully elucidated if these molecular abnormalities are the cause or consequence of an altered governing mood structure. In fact, the recent developments based on neuroimaging technologies have permitted in vivo characterization of the anatomical, physiological, and neurochemical correlates of mood disorders. This has resulted in neurocircuitry-based models in which both functional and structural brain pathology play a role in the development of mood alterations (Irani et al., 2007, Konarski et al., 2007). In particular, medial prefrontal cortex (PFC) and related limbic structures are related to disturbances of emotional processing (Lee et al., 2008), cognitive performance (Goto and Grace, 2005), neurotransmission (Murase et al., 1993), autonomic regulation (Carney et al., 2005), and neuroendocrine responses (Gold et al., 2002). Finally, these alterations are associated to mood disorders in a complex perspective integrating neurological, psychiatric, and immunological aspects (Drevets et al., 2008). In the light of this model, it is likely that a significant sub-population of depressed older adults may have depressive symptoms reflecting brain impairment and represent a serious risk for neurodegenerative diseases or neural injury.
Several susceptibility genetic factors could influence the development of LLD and AD. Genetic polymorphisms of the pro-inflammatory cytokine interleukin (IL) 1-beta promoter (McCulley et al., 2004) or brain-derived neurotrophic factor (BDNF) have been found to play a role in the susceptibility to both LLD and AD (Borroni et al., 2009). These genetic association studies provide support to the view that there is a relationship between LLD and AD. In fact, these conditions may share common risk factors and neuropathological processes like enhanced oxidative stress and neuroinflammation. Despite many psychological and biological theories regarding the pathogenesis of mood disorders, the possible etiologies of LLD and molecular aspects of cognitive impairment in LLD remain largely unknown and are still under investigation.
Some studies suggest that untreated or recurrent depression is associated with volume loss in the hippocampus (Potter and Steffens, 2007), with an increased inflammatory status (so-called the cytokine hypothesis of depression) (de Beaurepaire, 2002), possibly contributing to the dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis (Sapolsky, 2001). Recently, neurobiological studies on depression have focused the attention on a number of non-monoamine neurotransmitters and neuromodulators (Manji et al., 2001, Baker and Mitchell, 2009). In particular, those involving the excitatory Glu have opened the most exciting avenues of investigation for future psychopharmacology treatment (Covington et al., 2010). An impaired glutamatergic transmission, due for example to significantly lower expression of functional subunits of N-methyl-d-Aspartate (NMDA) receptor transcript (NR2A and NR2B glutamate-binding subunits) (Hynd et al., 2004), is not only involved in pathophysiology of AD (Jacob et al., 2007) but also in neurogenesis, neurite outgrowth, synaptogenesis, and neuronal cell death by a delicate interplay with neurotrophic factors (Mattson, 2008). Furthermore, many attempts have been made to elucidate the mechanisms underlying the onset of specific cognitive deficits in patients with LLD, but they still remain unclear. In the present review article, we examined the neurobiological bases of the relationship between late-life depressive disorders and AD, with a particular attention to glutamatergic pathway signaling like a bridge connecting these two conditions. In addition, attempts have been made to explain changes in glutamatergic pathway in LLD and dementia through the analysis of signal transduction mechanisms associated with these disabling diseases.
Section snippets
The glutamatergic system in the brain
Glu is the most abundant excitatory neurotransmitter in the brain (approximately 8–10 mM/kg) and it is found in more than 80% of all neurons (Gao and Bao, 2011). Because Glu cannot pass through the blood-brain barrier (BBB), it must be produced centrally in the neurons and glial cells (Mitchell and Baker, 2010). In the normal brain, Glu operates in balance with GABA and GABAergic neurons synapse on glutamatergic neurons to modulate their activity (Zarate et al., 2010). Glu acts on three
Late-life depression and glutamatergic system dysfunction
The monoamine hypothesis, which postulates dysfunctional noradrenergic and serotonergic systems as the underlying primary cause of depression, has been valuable for the development of conventional antidepressants, which can reverse these dysfunctional states to some degree. However, recent data from various neuroscience disciplines have questioned the major role of amines in the pathogenesis of depression. Unlike the monoamine transmitters that occupy about 5% of the total synapses in the
Alzheimer's disease and glutamatergic/GABA synapse impairment
Approximately 20–40% of cognitively normal older people have evidence of significant brain Aβ accumulation, supporting the principle that the presence of Aβ, even in high amount, is not sufficient to cause AD (Aizenstein et al., 2008, Peskind et al., 2006), and the cognitive decline curve might be closer to the Aβ curve deposition in individuals with comorbidities (Jack et al., 2010). There is also compelling evidence that Aβ deposition is associated with a local inflammatory response, which is
Interplay among cannabinoid, glutamate, and dopamine receptors in neuronal-glia synapses
It is well known that coordinated cross-talk among various receptors is essential for normal synaptic function. This interplay involves various neurotransmitters, neuropeptides, growth factors, and lipid mediators like eicosanoids, ECs, PAF, and their receptors (Farooqui, 2009). Thus, in the CNS, ECs have an important role as regulators of synaptic transmission by their action as activity dependent retrograde inhibitors of neurotransmitter release. The presence of cannabinoid receptors CB1 in
Modulation of glutamatergic and GABAergic neurotransmission: possible role of the diet in preventing depressive and neurodegenerative changes
The effect of diet on human health has been amply reported in many population-based studies and randomized clinical trials, providing evidence that a dietary pattern rich in some food groups with nutraceutical properties can reduce the incidence of all the main clinical outcomes, including neurodegenerative diseases (Frisardi et al., 2010). In fact, a high dietary intake of fish has been linked to decreased AD risk, presumably, for the favorable effects of fish oil on cerebrovascular function,
Conclusions
LLD and AD are serious disabling diseases affecting older population with high rate of physical and cognitive dysfunction, increased mortality, and unwarranted use of health care resources. If the cognitive changes occur as a consequence of depression or as a co-existing condition there is still under investigation. Although genetic, environmental, and social components are contributing factors of both these disorders, the neurobiological bases linking LLD and AD are largely unknown. An
Financial disclosures
All authors reported no biomedical financial interests or potential conflicts of interest. The funding agencies had no role in design or conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript.
Acknowledgment
This work was fully supported by the “Ministero della Salute”, IRCCS Research Program, Ricerca Corrente 2009–2011, Linea n. 2 “Malattie complesse”.
References (118)
- et al.
Decrease in neuron size in docosahexaenoic acid-deficient brain
Pediatr. Neurol.
(2002) - et al.
Depression-like phenotype following chronic CB1 receptor antagonism
Neurobiol. Dis.
(2010) - et al.
Role of BDNF Val66Met functional polymorphism in Alzheimer's disease-related depression
Neurobiol. Aging
(2009) - et al.
Metabotropic glutamate receptor 5 antagonist-induced stimulation of hypothalamic-pituitary-adrenal axis activity: interaction with serotonergic systems
Neuropharmacology
(2003) - et al.
Forecasting the global burden of Alzheimer's disease
Alzheimers Dement.
(2007) - et al.
Memories of NMDA receptors and LTP
Trends Neurosci.
(1995) - et al.
From synapse to nucleus: novel targets for treating depression
Neuropharmacology
(2010) - et al.
GABAB receptors and depression: current status
Adv. Pharmacol.
(2010) Questions raised by the cytokine hypothesis of depression
Brain Behav. Immun.
(2002)- et al.
Cannabinoid receptor 1 (CNR1) gene: impact on antidepressant treatment response and emotion processing in major depression
Eur. Neuropsychopharmacol.
(2008)
Role of metabotropic glutamate receptors in the control of neuroendocrine function
Neuropharmacology
GluR5-mediated signalling reduces hypothalamo-pituitary-adrenocortical stress responses at the paraventricular nucleus and median eminence
Psychoneuroendocrinology
Essential fatty acids, lipid membrane abnormalities, and the diagnosis and treatment of schizophrenia
Biol. Psychiatry
Low cerebrospinal fluid glutamate and glycine in refractory affective disorder
Biol. Psychiatry
New insights into the role of cortisol and the glucocorticoid receptor in severe depression
Biol. Psychiatry
Inhibition of astroglial glutamate transport by polyunsaturated fatty acids: evidence for a signalling role of docosahexaenoic acid
Neurochem. Int.
Fish consumption and major depression
Lancet
Hypothetical model of dynamic biomarkers of the Alzheimer's pathological cascade
Lancet Neurol.
Phosphorylation of the AMPA receptor GluR1 subunit is required for synaptic plasticity and retention of spatial memory
Cell
Neural correlates of affective processing in response to sad and angry facial stimuli in patients with major depressive disorder
Prog. Neuropsychopharmacol. Biol. Psychiatry
A meta-analytic review of polyunsaturated fatty acid compositions in patients with depression
Biol. Psychiatry
Role of omega-3 fatty acids in brain development and function: potential implications for the pathogenesis and prevention of psychopathology
Prostaglandins Leukot. Essent. Fatty Acids
Glutamate as a neurotransmitter in the brain: review of physiology and pathology
J. Nutr.
Correlation between plasma levels of glutamate, alanine and serine with severity of depression
Prog. Neuropsychopharmacol. Biol. Psychiatry
Prefrontal cortex regulates burst firing and transmitter release in rat mesolimbic dopamine neurons studied in vivo
Neurosci. Lett.
Metabotropic glutamate receptor ligands as possible anxiolytic and antidepressant drugs
Pharmacol. Ther.
Late-life depression, mild cognitive impairment, and dementia: possible continuum?
Am. J. Geriatr. Psychiatry
Effective electroconvulsive therapy reverses glutamate/glutamine deficit in the left anterior cingulum of unipolar depressed patients
Psychiatry Res.
Mood disorders: regulation by metabotropic glutamate receptors
Biochem. Pharmacol.
Reductions in neuronal and glial density characterize the dorsolateral prefrontal cortex in bipolar disorder
Biol. Psychiatry
Endogenous activation of group-II metabotropic glutamate receptors inhibits the hypothalamic-pituitary-adrenocortical axis
Neuropharmacology
Frequent amyloid deposition without significant cognitive impairment among the elderly
Arch. Neurol.
The course of geriatric depression with “reversible dementia”: a controlled study
Am. J. Psychiatry
Plasma and platelet excitatory amino acids in psychiatric disorders
Am. J. Psychiatry
Alzheimer's disease facts and figures
Alzheimers Dement.
Diagnostic and Statistical Manual of Mental Disorders
Plasticity of glutamate and GABAA receptors in the hippocampus of patients with Alzheimer's disease
Cell. Mol. Neurobiol.
Depression: clinical mechanisms
Glutamate release from activated microglia requires the oxidative burst and lipid peroxidation
J. Neurochem.
Low GABA concentrations in occipital cortex and anterior cingulate cortex in medication-free, recovered depressed patients
Int. J. Neuropsychopharmacol.
Pathways linking late-life depression to persistent cognitive impairment and dementia
Dialogues Clin. Neurosci.
Docosahexaenoic acid promotes hippocampal neuronal development and synaptic function
J. Neurochem.
Depression, the autonomic nervous system, and coronary heart disease
Psychosom. Med.
Regulation of neurotransmitter release by metabotropic glutamate receptors
J. Neurochem.
Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene
Science
Non-monoamine-based approach for the treatment of depression and anxiety disorders
Recent Patents C. N. S. Drug Discov.
Altered cortical glutamatergic and GABAergic signal transmission with glial involvement in depression
Proc. Natl. Acad. Sci. U. S. A.
Proteases and proteolysis in Alzheimer disease: a multifactorial view on the disease process
Physiol. Rev.
Brain structural and functional abnormalities in mood disorders: implications for neurocircuitry models of depression
Brain Struct. Funct.
The anticonvulsants lamotrigine, riluzole, and valproate differentially regulate AMPA receptor membrane localization: relationship to clinical effects in mood disorders
Neuropsychopharmacology
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