Progress in Neurobiology 91 (2010) 362–375 Contents lists available at ScienceDirect Progress in Neurobiology journal homepage: www.elsevier.com/locate/pneurobio The putative neurodegenerative links between depression and Alzheimer’s disease Suthicha Wuwongse a,b, Raymond Chuen-Chung Chang b,c,d,*, Andrew C.K. Law a,c,d,** a Department of Psychiatry, LKS Faculty of Medicine, Hong Kong b Laboratory of Neurodegenerative Diseases, Department of Anatomy, LKS Faculty of Medicine, Hong Kong c Research Centre of Heart, Brain, Hormone and Healthy Aging, LKS Faculty of Medicine, Hong Kong d State Key Laboratory of Brain and Cognitive Sciences, The University of Hong Kong, Pokfulam, Hong Kong ARTICLE INFO ABSTRACT Article history: Alzheimer’s disease (AD) is the leading neurodegenerative cause of dementia in the elderly. Thus far, Received 11 September 2009 there is no curative treatment for this devastating condition, thereby creating significant social and Received in revised form 16 April 2010 medical burdens. AD is characterized by progressive cognitive decline along with various Accepted 27 April 2010 neuropsychiatric symptoms, including depression and psychosis. Depression is a common psychiatric disorder affecting individuals across the life span. Although the Keywords: ‘‘monoamine hypothesis’’ of depression has long been proposed, the pathologies and mechanisms for Alzheimer’s disease depressive disorders remain only partially understood. Pharmacotherapies targeting the monoaminer- Depression gic pathways have been the mainstay in treating depression. Additional therapeutic approaches focusing Neuroinflammation Brain-derived nerve growth factor other pathological mechanisms of depression are currently being explored. Neurodegeneration Interestingly, a number of proposed mechanisms for depression appear to be similar to those Cortisol implicated in neurodegenerative diseases, including AD. For example, diminishing neurotrophic factors and neuroinflammation observed in depression are found to be associated with the development of AD. This article first provides a concise review of AD and depression, then discusses the putative links between the two neuropsychiatric conditions. ß 2010 Elsevier Ltd. All rights reserved. Contents 1. Alzheimer’s disease . 363 1.1. Clinical and pathological features of AD . 363 1.1.1. Pathogenic factors for AD . 363 1.1.2. From cholinergic neurons to glutamatergic neurons in AD . 364 1.1.3. Neurodegenerative processes in AD . 364 1.2. Treatment of AD . 364 1.2.1. Current available treatments. 365 1.2.2. Therapeutic research directions . 365 Abbreviations: 5HTT, serotonin transporter; Ab, amyloid beta; ACh, acetylcholine; AChE-I, acetylcholinesterase inhibitor; ACTH, adrenocorticotropic hormone; AD, Alzheimer’s disease; AMPA, a-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate; APP, amyloid precursor protein; BACE1, b-site APP cleaving enzyme; BDNF, brain derived neurotrophic factor; BuChE, butyrylcholinesterase; CREB, cAMP response element binding protein; CRH, corticotropin releasing hormone; GSK-3b, glycogen synthase kinase-3 beta; HPA, hypothalamus-pituitary-adrenal; IDO, indoleamine-pyrrole 2,3-dioxygenase; IFNg, interferon gamma; IFNa, interferon alpha; IL-1b, interleukin 1 beta; IL-6, interleukin 6; MAO-A, monoamine oxidase A; MAO-B, monoamine oxidase B; MAOI, monoamine oxidase inhibitor; MAPK, mitogen activated protein kinase; MDD, major depressive disorder; NFT, neurofibrillary tangles; NGF, nerve growth factor; NMDA, N-methyl-D-aspartic acid; NFkB, nuclear factor kappa-light-chain- enhancer of activated B cells; PD, Parkinson’s disease; PS1, presenilin 1; SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressant; TLR, toll-like receptor; TNFa, tumor necrosis factor alpha; TGFb, transforming growth factor beta. * Corresponding author at: Department of Anatomy, The University of Hong Kong, Rm. L1-49, Laboratory Block, Faculty of Medicine Building, 21 Sassoon Road, Pokfulam, Hong Kong. Tel.: +852 2819 9127; fax: +852 2817 0857. ** Corresponding author at: Department of Psychiatry, The University of Hong Kong, Room 219, Block J, Queen Mary Hospital, 102 Pokfulam Road, Pokfulam, Hong Kong. Fax: +852 2819 3851. E-mail addresses: [email protected] (R.-C. Chang), [email protected] (Andrew C.K. Law). 0301-0082/$ – see front matter ß 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.pneurobio.2010.04.005 S. Wuwongse et al. / Progress in Neurobiology 91 (2010) 362–375 363 2. Depression . 365 2.1. Clinical and pathological features of depression . 365 2.1.1. HPA axis dysregulation . 366 2.1.2. Dysregulation of monoaminergic neurotransmitters . 366 2.1.3. Involvement of inflammation and neurotrophic factor deficiency in depression . 366 2.2. Antidepressants. 367 2.2.1. Existing depression pharmacotherapy . 367 2.2.2. Antidepressant research directions. 367 3. Depression and Alzheimer’s disease . 367 3.1. Epidemiological observations . 367 3.2. Genetic studies . 367 3.3. Pathological and biochemical linkage . 369 3.4. Clinical investigation . 370 4. Summary....................................................................................................... 371 Acknowledgements . 371 References...................................................................................................... 371 1. Alzheimer’s disease Ab plaques and NFT are the most prominent histological features in the AD brain. NFT are positively associated with clinical Alzheimer’s disease (AD) is the most common neurodegenerative severity in AD patients, estimated by the Clinical Dementia Rating form of dementia. Aging is the most important risk factor for AD. The and Mini-Mental State Examination scores (Giannakopoulos et al., prevalence of AD is approximately 7–10% in individuals over the age 2003; Gold et al., 2001). On the other hand, studies regarding the of 65 and increases to about 40% over the age of 80. AD is incurable clinical correlations of Ab plaques are equivocal (Gold et al., 2001). and increases the mortality rate by approximately 40% in men and Ab and NFT trigger a number of mechanisms leading to neuronal women. The number of people who have AD is expected to double death. Altered cholinergic and glutamatergic neurotransmission, every 20 years, thereby constituting significant medio- and socio- apoptosis, oxidative stress, calcium homeostasis dysfunction, and economical burdens (Alzheimer’s Association, 2009). neuroinflammation are some of the proposed mechanisms Several genetic risk factors have been identified in AD. implicated in the AD pathogenesis. Mutations in the amyloid precursor protein (APP) gene on chromosome 21, presenilin 1 (PS1) on chromosome 14, and 1.1.1. Pathogenic factors for AD presenilin 2 on chromosome 1 have been found to be responsible Ab is believed to play a central role in the pathogenesis of AD. for the early-onset, autosomal dominant forms of AD (Levy-Lahad Extracellular Ab plaques found in AD brains are surrounded by et al., 1995; St George-Hyslop et al., 1987; Van Broeckhoven et al., dystrophic dendrites and axons, activated microglia, and reactive 1992). Alternatively, the epsilon 4 variant of apolipoprotein E gene astrocytes (Gomez-Isla et al., 2008). located on chromosome 19 has been found to be involved in the Ab is an abnormal by-product of the cleavage of APP. APP is a late-onset, sporadic form of the disease (Utermann, 1994). These transmembrane protein having roles in neuronal protection and genetic factors influence the pathology of AD by enhancing the development (Turner et al., 2003). APP is cleaved by a, b,andg- accumulation and aggregation of amyloid b (Ab) and neurofibril- secretases. APP can undergo two cleavage pathways: amyloido- lary tangles (NFT) (Selkoe, 2001; Williamson et al., 2009). Other genic and non-amyloidogenic, depending on the cleaving important candidate genes include death associated protein kinase enzymes involved. When APP is cleaved by a-secretase followed 1—an enzyme involved in neuronal apoptosis; insulin-degrading by g-secretase, the possibility of Ab formation is eliminated, as enzyme gene responsible for producing insulin degrading enzyme, a-secretase mediated cleavage occurs within the Ab region which is involved in the degradation and clearance of Ab; and (Sisodia, 1992). Under the ‘‘amyloidogenic’’ condition, APP is growth factor receptor-bound 2 associated binding protein, which first cleaved by b-secretase followed by the g-secretase was found to be overexpressed in pathologically vulnerable cleavage, thereby releasing the neurotoxic 40 to 42 amino acid neurons and its expression increases tau hyperphosphorylation peptidic fragments. b-site APP cleaving enzyme 1 (BACE1) and (Bertram et al., 2000; Li et al., 2006; Reiman et al., 2007). More presenilins have been suggested to be the major constituents of recently, the neuronal sortilin-related receptor gene on chromo- b-andg-secretases, respectively (Hampel and Shen, 2009; some 11, has been shown in several studies to be associated with Thinakaran et al., 1996; Vassar, 2004). Recent studies show that AD (Rogaeva et al., 2007; Webster et al., 2008). oligomeric Ab are also neurotoxic. These findings suggest that Ab-mediated neurotoxicity could be an early pathological event 1.1. Clinical and pathological features of AD leading to neuronal demise in AD (Pereira et al., 2005; Schott et al., 2006). The primary clinical presentation of AD is progressive cognitive Intraneuronal NFT are composed of hyperphosphorylated tau decline, with memory loss being a relatively early sign of the proteins