Depression and Alzheimer's disease: Neurobiological links and common pharmacological targets

Caraci, Filippo; Copani, Agata; Nicoletti, Ferdinando; Drago, Filippo

doi:10.1016/j.ejphar.2009.10.022

Cited by 248 publications

(172 citation statements)

References 138 publications

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“…Knockout of p75NTR in APPtransgenic mice reduces the Aβ production in the brain, suggesting that activation of p75NTR in Aβ-related pa- Aβ Down-regulation of BDNF [9] , activation of inflammatory cells [10] , generation of reactive oxygen species [11] , inhibition of long-term potentiation [6] , impairment of synaptic structure and function [7,8] , acceleration of neurofibrillary tangle formation [12] Altered function of blood-brain barrier Decreased clearance of Aβ [13] , leakage of serum-derived components into brain leading to neuronal dysfunction [14] , promotion of aluminum accumulation in brain [15] Brain trauma Increased risk of AD [16,17] Chronic stress Induction of abnormal hyperphosphorylation of tau [18] , accelerated impairment of cognition [19] Decline in protein synthesis Further neuronal impairment caused by other factors [20,21] Decline in stimulation and acetylcholine Impaired memory circuitry [22,23] Decreased levels of neurotrophic factors Deficient support for neuronal survival [24,25] Depression Chronic inflammation, impairment in the signaling of neurotrophins [26] Diabetes Apoptosis of neurons, defects of long-term potentiation, changed synapse plasticity [27,28] Downregulation of neprilysin Promotion of Aβ deposits [29][30][31] Enhanced reactive oxygen species levels Contributes to mitochondrial dysfunction [32,33] and calcium overload…”

Section: Ntf Deficits Cause Aβ Overloadmentioning

confidence: 99%

Combination of Aβ clearance and neurotrophic factors as a potential treatment for Alzheimer’s disease

et al. 2012

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There is no effective drug to treat Alzheimer's disease (AD), a neurodegenerative disease affecting an estimated 30 million people around the world. Strongly supported by preclinical and clinical studies, amyloid-beta (Aβ) may be a target for developing drugs against AD. Meanwhile, the fact that localized neuronal death/loss and synaptic impairment occur in AD should also be considered. Neuronal regeneration, which does not occur normally in the mammalian central nervous system, can be promoted by neurotrophic factors (NTFs). Evidence from clinical trials has shown that both Aβ clearance and NTFs are potentially effective in treating AD, thus a new approach combining Aβ clearance and administration of NTFs may be an effective therapeutic strategy.Keywords: Alzheimer's disease; amyloid-beta; neurotrophic factors; treatment IntroductionAlzheimer's disease (AD) is an age-related, progressive and irreversible neurodegenerative disease that causes serious cognitive dysfunction. Its pathological hallmarks are extracellular deposits of amyloid-beta (Aβ) and intracellular neurofibrillary tangles, together with drastic synaptic and neuronal reduction or loss [1] . It has been estimated that AD affects 30 million people around the world [2] , and the past two decades have witnessed an explosion in research into the underlying mechanisms as well as potential therapeutic strategies. Although it was first described by German psychiatrist Alois Alzheimer in 1906, there is still no cure for AD, partly because the cellular and molecular mechanisms underlying it are far from clear. The Food and Drug Administration in the United Stateshas approved a limited range of drugs to treat AD, including acetylcholinesterase inhibitors (AChEIs) and N-methyl-Daspartate receptor (NMDAR) antagonists [3] , although their effects are merely symptomatic and memory-improvement occurs within a limited period. Donepezil, galantamine, rivastigmine and tacrine are AChEIs that prevent the breakdown of acetylcholine released from presynaptic terminals, increasing the residence time of the neurotransmitter within the synapse and thereby prolonging the duration of its interaction with postsynaptic receptors [4] . Memantine, an NMDAR antagonist, has been approved for the treatment of moderate and severe AD; it works by preventing the excitatory neurotoxicity induced by excessive glutamate [5] .Currently, no available pharmacological agents cure or reverse the progression of this devastating neurological disorder. It is therefore urgent to improve our understanding of its pathogenesis, and then develop an effective treatment strategy. This review aimed to provide insights Neurosci Bull February 1, 2013, 29(1): 111-120 112 into the design of potentially effective pharmaceutical treatments for AD by targeting two seemingly separate but tightly connected components, Aβ and neurotrophic factors (NTFs). Aβ as a Promising Target for AD TreatmentAβ is a peptide of 36-43 amino-acids produced from amyloid precursor protein (APP) through aberrant cleavage by...

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Section: Ntf Deficits Cause Aβ Overloadmentioning

confidence: 99%

Combination of Aβ clearance and neurotrophic factors as a potential treatment for Alzheimer’s disease

et al. 2012

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“…A lifetime history of major depression has been considered as a risk factor for later development of Alzheimer's disease [124,125]. The presence of depressive symptoms can affect the conversion of mild cognitive impairment to Alzheimer's disease.…”

Section: Depressionmentioning

confidence: 99%

“…On the other hand, neuro-degenerative phenomena have been observed in different brain regions of patients with a history of depression. Recent evidence suggests that molecular mechanisms and cascades that underlie the pathogenesis of major depression, such as chronic inflammation and hyper-activation of hypothalamic-pituitary-adrenal (HPA) axis, are also involved in the pathogenesis of Alzheimer's disease [125]. A recent study has shown that depression increased the risk of dementia among patients with diabetes [126].…”

Section: Depressionmentioning

confidence: 99%

Epidemiology of Alzheimer’s Disease

Xu¹,

Ferrari²,

Wang³

2013

Understanding Alzheimer's Disease

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“…Neurotrophins are small proteins that play significant roles in maintaining neuronal survival and axonal guidance. Brain-derived neurotrophic factor (BDNF) is one neurotrophin whose level has been linked to impaired cognition, depression and AD [6].…”

Section: Introductionmentioning

confidence: 99%