Antidepressants are a rational complementary therapy for the treatment of Alzheimer's disease

There is a high prevalence rate (30-50%) of Alzheimer's disease (AD) and depression comorbidity. Depression can be a risk factor for the development of AD or it can be developed secondary to the neurodegenerative process. There are numerous documented diagnosis and treatment challenges for the patients who suffer comorbidity between these two diseases. Meta analysis studies have provided evidence for the safety and efficacy of antidepressants in treatment of depression in AD patients. Preclinical and clinical studies show the positive role of chronic administration of selective serotonin reuptake inhibitor (SSRI) antidepressants in hindering the progression of the AD and improving patient performance. A number of clinical studies suggest a beneficial role of combinatorial therapies that pair antidepressants with FDA approved AD drugs. Preclinical studies also demonstrate a favorable effect of natural antidepressants for AD patients. Based on the preclinical studies there are a number of plausible antidepressants effects that may modulate the progression of AD. These effects include an increase in neurogenesis, improvement in learning and memory, elevation in the levels of neurotrophic factors and pCREB and a reduction of amyloid peptide burden. Based on this preclinical and clinical evidence, antidepressants represent a rational complimentary strategy for the treatment of AD patients with depression comorbidity.     

Berberine as a promising natural compound for the treatment of periodontal disease: A focus on anti-inflammatory properties

Accumulating evidence during the last two decades has addressed the potential anti-inflammatory properties of berberine (BBR), a bioactive alkaloid compound isolated from Coptidis rhizoma, in controlling or treating several inflammatory diseases. Periodontitis is one of the most common chronic and serious inflammatory diseases, in which uncontrolled and unabated host immune responses against periodontopathic pathogens play critical and crucial roles in the disease pathogenesis. Hence, regulating inflammatory responses in periodontitis has a valuable approach and holds promise in treating periodontitis. For the first time, this paper reviews the evidence from in vitro and in vivo experimental models to explore the anti-inflammatory effects of BBR in periodontitis and exhibits that BBR has the high potency to exert anti-inflammatory effects by reducing expression and secretion of pro-inflammatory mediators including TNF-α, IL-1β, IL-17, RANKL, MMP-2, MMP-9 and MCP-1. The BBR-mediated anti-inflammatory actions could translate into the inhibition of the periodontal tissues and alveolar bone destruction and the control of the disease in vivo. As the second aim of this paper, we also paid attention to the therapeutic potential of BBR in treating human diseases regarding its anti-inflammatory properties.     

肠道菌群-阿尔茨海默病防治的新靶标

阿尔茨海默病(Alzheimer's disease,AD)是一种渐进性中枢神经系统退行性疾病,其发病机制仍未完全阐明.近年来,随着菌群-肠-脑轴研究的兴起,肠道菌群在AD发生和发展中的作用日益得到重视.本文综述了AD患者的肠道菌群特征,肠道菌群影响AD的主要途径及益生菌、抗生素和饮食等对AD患者的干预作用,为制定靶向...     

Retinoids for treatment of Alzheimer's disease

Retinoids are Vitamin A derivatives involved in cellular regulatory processes including cell differentiation, neurite outgrowth and defense against oxidative stress. Retinoids may also influence Amyloid beta processing upregulation of alpha secretase via ADAM10. Vitamin A and other retinoids also directly inhibit formation of Amyloid fibrils in vivo. These properties of retinoids are relevant to theories of Alzheimer's disease pathogenesis. Retinoids are already used in treatment of acne vulgaris, psoriasis, neuroblastoma and acute promyelocytic leukemia. Clinical studies involving in cognitively impaired older adults with Alzheimer's disease are beginning with a variety of retinoids. These studies need to address safety issues of retinoids in older populations, and hold hope for demonstrating efficacy in translating these basic mechanisms to treatment of a widespread dementing illness.     

β淀粉样蛋白的分泌酶与阿尔采末病的治疗

β淀粉样蛋白(Aβ)级联反应在阿尔采末病(AD)发病过程中起主要作用,Aβ由分泌酶中的β和γ分泌酶水解β淀粉样蛋白前体蛋白(APP)而来。本文综述了参与APP水解的三种分泌酶(α、β和γ)的发现、研究进展及其在调节β淀粉样蛋白过程中的作用。选择性地激活α分泌薄或抑制β和γ分泌酶格减少Aβ产生,为AD治疗提供新的研究思路,以分泌酶为靶点可能成为治疗AD的理想途径。     

Secretases as targets for the treatment of Alzheimer's disease

Alzheimer's disease (AD) is the major cause of dementia in most developed countries. Treatment to modify this disease is currently unavailable, but needed urgently. The amyloid-cascade hypothesis proposes that amyloid beta-peptide (Abeta), found in the plaques characteristic of AD, plays an early, critical role in the disease process. It follows that preventing the generation of Abeta could be therapeutically useful in all cases of AD. Inhibition of the secretases that produce Abeta from a large precursor protein is the main approach to achieve this goal.     

Beta-amyloid treatment of two complementary P301L tau-expressing Alzheimer's disease models reveals similar deregulated cellular processes

Alzheimer's disease (AD) is characterized by Abeta peptide-containing plaques and tau-containing neurofibrillary tangles (NFTs). Both pathologies have been combined by crossing Abeta plaque-forming APP mutant mice with NFT-forming P301L tau mutant mice or by stereotaxically injecting beta-amyloid peptide 1-42 (Abeta42) into brains of P301L tau mutant mice. In cell culture, Abeta42 induces filamentous tau aggregates. To understand which processes are disrupted by Abeta42 in the presence of tau aggregates, we applied comparative proteomics to Abeta42-treated P301L tau-expressing neuroblastoma cells and the amygdala of P301L tau transgenic mice stereotaxically injected with Abeta42. Remarkably, a significant fraction of proteins altered in both systems belonged to the same functional categories, i.e. stress response and metabolism. We also identified model-specific effects of Abeta42 treatment such as differences in cell signaling proteins in the cellular model and of cytoskeletal and synapse associated proteins in the amygdala. By Western blotting (WB) and immunohistochemistry (IHC), we were able to show that 72% of the tested candidates were altered in human AD brain with a major emphasis on stress-related unfolded protein responsive candidates. These data highlight these processes as potentially important initiators in the Abeta42-mediated pathogenic cascade in AD and further support the role of unfolded proteins in the course of AD.     

Chronic ramelteon treatment in a mouse model of Alzheimer's disease

Prior research has reported beneficial effects of melatonin in rodent models of Alzheimer's disease (AD). This study evaluated the effect of ramelteon (Rozerem, a melatonin receptor agonist) on spatial learning & memory and neuropathological markers in a transgenic murine model of AD (the B6C3-Tg(APPswe,PSEN1dE9)85Dbo/J transgenic mouse strain; hereafter 'AD mice'). Three months of daily ramelteon treatment (~3mg/kg/day), starting at 3 months of age, did not produce an improvement in the cognitive performance of AD mice (water maze). In contrast to wild-type control mice, AD mice did not show any evidence of having learned the location of the escape platform. The cortex and hippocampus of AD mice contained significant quantities of beta-amyloid plaques and PARP-positive (poly ADP ribose polymerase) cells, indicating apoptosis. Six months of ramelteon treatment, starting at 3 months of age, did not produce any change in these neuropathological markers. The ability of long term melatonin treatment to improve cognition and attenuate neuropathology in AD mice did not generalize to this dosage of ramelteon.     

Presenilins as therapeutic targets for the treatment of Alzheimer's disease

Studies demonstrating that accumulation and aggregation of the amyloid beta protein (Abeta) within the brain is likely to cause Alzheimer's disease (AD) have provided the rationale for therapeutic strategies aimed at influencing Abeta production, aggregation and clearance. gamma-secretase catalyzes the final cleavage that releases the Abeta from its precursor; therefore, it is a potential therapeutic target for the treatment of AD. Recent data show that the polytopic membrane proteins presenilin 1 and presenilin 2 are either catalytic components or essential co-factors of a membrane-bound proteolytic complex that possesses gamma-secretase activity. Although recent findings demonstrating that gamma-secretase inhibitors bind directly to presenilins (PSs) further support a catalytic role for PSs in gamma-secretase cleavage, additional studies are still needed to clarify the role of PSs in gamma-secretase cleavage and the use of targeting PSs to reduce Abeta production.     

In search of a treatment for Alzheimer's disease and potential immunonosuppresive therapeutic interventions

Alzheimer's disease (AD) is a serious neurodegenerative disease of aging. Recent projections of the dramatic increase in AD incidence worldwide by 2050 reveal its magnitude as a world-wide health crisis and underscore the urgent need to understand the etiology of AD in order to develop therapeutic interventions. A popular debate among scientists has traditionally pitted those in support of Beta amyloid protein as a causative factor ("Baptists") against others who implicate tau hyperphosphorylation ("Tauists"). Considering the significance of Beta amyloid protein and hyperphosphorlyated tau protein aggregates in AD pathology, this article delves into the nature of inflammation associated with these aggregates. Aspects of inflammation focus on microglia, resident immune cells of the CNS that are activated during AD inflammation and are known to play a significant role in pathogenesis. This article discusses the role of microglia, inflammation, and the immune response as a middle ground in the debate between the "Tauists" and the "Baptists" respective positions. It explores recent advances in immunotherapy and supports continued research in and use of immunosuppressive regimens as potential therapeutic interventions for AD.     

Immunotherapeutic strategies for prevention and treatment of Alzheimer's disease.

Pathologic examination in Alzheimer's disease (AD) shows a significant correlation between beta-amyloid peptide (AbetaP) deposition and the clinical severity of dementia. Formation of beta-amyloid (Abeta) is a complex kinetic and thermodynamic process, dependent on peptide-peptide interactions that may be modulated by other proteins. We found that site-directed antibodies toward peptide EFRH sequences 3-6 of the N-terminal region of AbetaP suppress in vitro formation of Abeta and dissolve already-formed fibrillar amyloid. These so-called chaperone-like properties of monoclonal antibodies led to the development of a new immunologic approach to AD treatment. The immunization procedure, based on phages displaying the EFRH epitope as antigen, induced anti-AbetaP antibodies that recognized the whole AbetaP and exhibited antiaggregating properties similar to those of antibodies obtained by injection of Abeta fibrils. Production and performance of anti-beta-amyloid antibodies in the transgenic mouse model of AD showed that these antibodies may be delivered from the periphery to the central nervous system, preventing the formation of Abeta and dissolving already-present aggregates. Moreover, immunization with Abeta protected transgenic mice from the learning and age-related memory deficits that occur in AD. These data support the hypotheses that Abeta plays a central role in AD and that site-directed antibodies that modulate Abeta conformation may provide immunotherapy of the disease.     

Tannic acid as a natural antioxidant compound: Discovery of a potent metabolic enzyme inhibitor for a new therapeutic approach in diabetes and Alzheimer's disease

Multiple studies have been recorded on the synthesis and design of multi‐aim anti‐Alzheimer molecules. Using dual butyrylcholinesterase/acetylcholinesterase inhibitor molecules has attracted more interest in the therapy for Alzheimer's disease. In this study, a tannic acid compound showed excellent inhibitory effects against acetylcholine esterase (AChE), α‐glycosidase, α‐amylase, and butyrylcholinesterase (BChE). IC₅₀ values of tannic acid obtained 11.9 nM against α‐glycosidase and 3.3 nM against α‐amylase, respectively. In contrast, K_i values were found of 50.96 ± 2.18 µM against AChE and 53.17 ± 4.47 µM against BChE. α‐Glycosidase inhibitor compounds can be utilized as a novel group of antidiabetic drugs. By competitively decreasing glycosidase activity, these inhibitor molecules help to hamper the fast breakdown of sugar molecules and thereby control the blood sugar level.     

Human fetal tau protein isoform: possibilities for Alzheimer's disease treatment

While early 1990s reports showed the phosphorylation pattern of fetal tau protein to be similar to that of tau in paired helical filaments (PHF) in Alzheimer's disease (AD), neither the molecular mechanisms of the transient developmental hyperphosphorylation of tau nor reactivation of the fetal plasticity due to re-expression of fetal protein kinases in the aging and AD human brain have been sufficiently investigated. Here, we summarize the current knowledge on fetal tau, adding new data on the specific patterns of tau protein and mRNA expression in the developing human brain as well as on change in tau phosphorylation in the perforant pathway after entorhinal cortex lesion in mice. As fetal tau isoform does not form PHF even in a highly phosphorylated state, understanding its expression and post-translational modifications represents an important avenue for future research towards the development of AD treatment and prevention.     

Implications for treatment: GABAA receptors in aging, Down syndrome and Alzheimer's disease

In addition to progressive dementia, Alzheimer's disease (AD) is characterized by increased incidence of seizure activity. Although originally discounted as a secondary process occurring as a result of neurodegeneration, more recent data suggest that alterations in excitatory-inhibitory (E/I) balance occur in AD and may be a primary mechanism contributing AD cognitive decline. In this study, we discuss relevant research and reports on the GABA(A) receptor in developmental disorders, such as Down syndrome, in healthy aging, and highlight documented aberrations in the GABAergic system in AD. Stressing the importance of understanding the subunit composition of individual GABA(A) receptors, investigations demonstrate alterations of particular GABA(A) receptor subunits in AD, but overall sparing of the GABAergic system. In this study, we review experimental data on the GABAergic system in the pathobiology of AD and discuss relevant therapeutic implications. When developing AD therapeutics that modulate GABA it is important to consider how E/I balance impacts AD pathogenesis and the relationship between seizure activity and cognitive decline.     

Simple model systems: a challenge for Alzheimer's disease

ABSTRACT: The success of biomedical researches has led to improvement in human health and increased life expectancy. An unexpected consequence has been an increase of age-related diseases and, in particular, neurodegenerative diseases. These disorders are generally late onset and exhibit complex pathologies including memory loss, cognitive defects, movement disorders and death. Here, it is described as the use of simple animal models such as worms, fishes, flies, Ascidians and sea urchins, have facilitated the understanding of several biochemical mechanisms underlying Alzheimer's disease (AD), one of the most diffuse neurodegenerative pathologies. The discovery of specific genes and proteins associated with AD, and the development of new technologies for the production of transgenic animals, has helped researchers to overcome the lack of natural models. Moreover, simple model systems of AD have been utilized to obtain key information for evaluating potential therapeutic interventions and for testing efficacy of putative neuroprotective compounds.     

The modulation of metal bio-availability as a therapeutic strategy for the treatment of Alzheimer's disease

The postmortem Alzheimer's disease brain is characterized histochemically by the presence of extracellular amyloid plaques and neurofibrillary tangles. Also consistent with the disease is evidence for chronic oxidative damage within the brain. Considerable research data indicates that these three critical aspects of Alzheimer's disease are interdependent, raising the possibility that they share some commonality with respect to the ever elusive initial factor(s) that triggers the development of Alzheimer's disease. Here, we discuss reports that show a loss of metal homeostasis is also an important event in Alzheimer's disease, and we identify how metal dyshomeostasis may contribute to development of the amyloid-beta, tau and oxidative stress biology of Alzheimer's disease. We propose that therapeutic agents designed to modulate metal bio-availability have the potential to ameliorate several of the dysfunctional events characteristic of Alzheimer's disease. Metal-based therapeutics have already provided promising results for the treatment of Alzheimer's disease, and new generations of pharmaceuticals are being developed. In this review, we focus on copper dyshomeostasis in Alzheimer's disease, but we also discuss zinc and iron.     

Diabetes as a risk factor for Alzheimer's disease: insulin signalling impairment in the brain as an alternative model of Alzheimer's disease

Surprisingly little is known about the mechanisms that trigger the onset of AD (Alzheimer's disease) in sporadic forms. A number of risk factors have been identified that may shed light on the mechanisms that may trigger or facilitate the development of AD. Recently, T2DM (Type 2 diabetes mellitus) has been identified as a risk factor for AD. A common observation for both conditions is the desensitization of insulin receptors in the brain. Insulin acts as a growth factor in the brain and is neuroprotective, activates dendritic sprouting, regeneration and stem cell proliferation. The impairment of this important growth factor signal may facilitate the development of AD. Insulin as well as other growth factors have shown neuroprotective properties in preclinical and clinical trials. Several drugs have been developed to treat T2DM, which re-sensitize insulin receptors and may be of use to prevent neurodegenerative processes in the brain. In particular, the incretins GLP-1 (glucagon-like peptide-1) and GIP (glucose-dependent insolinotropic polypeptide) are hormones that re-sensitize insulin signalling. Incretins also have similar growth-factor-like properties as insulin and are neuroprotective. In mouse models of AD, GLP-1 receptor agonists reduce amyloid plaque formation, reduce the inflammation response in the brain, protect neurons from oxidative stress, induce neurite outgrowth, and protect synaptic plasticity and memory formation from the detrimental effects caused by β-amyloid production and inflammation. Other growth factors such as BDNF (brain-derived neurotrophic factor), NGF (nerve growth factor) or IGF-1 (insulin-like growth factor 1) also have shown a range of neuroprotective properties in preclinical studies. These results show that these growth factors activate similar cell signalling mechanisms that are protective and regenerative, and suggest that the initial process that may trigger the cascade of neurodegenerative events in AD could be the impairment of growth factor signalling such as early insulin receptor desensitization.