Challenges for Alzheimer's Disease Therapy: Insights from Novel Mechanisms Beyond Memory Defects

Submitted by Sandra Infurna ([email protected]) on 2018-08-30T17:16:44Z No. of bitstreams: 1 rudimar_frozza_etal_IOC_2018.pdf: 758599 bytes, checksum: 720c7f134b1377b2857a73a92ff7b84f (MD5)Approved for entry into archive by Sandra Infurna ([email protected]) on 2018-08-30T17:23:36Z (GMT) No. of bitstreams: 1 rudimar_frozza_etal_IOC_2018.pdf: 758599 bytes, checksum: 720c7f134b1377b2857a73a92ff7b84f (MD5)Made available in DSpace on 2018-08-30T17:23:36Z (GMT). No. of bitstreams: 1 rudimar_frozza_etal_IOC_2018.pdf: 758599 bytes, checksum: 720c7f134b1377b2857a73a92ff7b84f (MD5) Previous issue date: 2018Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Rio de Janeiro, RJ. Brasil.Universidade Federal do Rio de Janeiro. Instituto de Bioquímica Médica Leopoldo de Meis. Rio de Janeiro, RJ, Brasil / Universidade Federal do Rio de Janeiro. Instituto de Biofísica Carlos Chagas Filho. Rio de Janeiro, RJ, Brasil.Universidade Federal do Rio de Janeiro. Instituto de Bioquímica Médica Leopoldo de Meis. Rio de Janeiro, RJ, Brasil / Queen’s University,. Centre for Neuroscience Studies. Department of Biomedical and Molecular Sciences. Kingston, Ontario, Canada.Alzheimer's disease (AD), the most common form of dementia in late life, will become even more prevalent by midcentury, constituting a major global health concern with huge implications for individuals and society. Despite scientific breakthroughs during the past decades that have expanded our knowledge on the cellular and molecular bases of AD, therapies that effectively halt disease progression are still lacking, and focused efforts are needed to address this public health challenge. Because AD is classically recognized as a disease of memory, studies have mainly focused on investigating memory-associated brain defects. However, compelling evidence has indicated that additional brain regions, not classically linked to memory, are also affected in the course of disease. In this review, we outline the current understanding of key pathophysiological mechanisms in AD and their clinical manifestation. We also highlight how considering the complex nature of AD pathogenesis, and exploring repurposed drug approaches can pave the road toward the development of novel therapeutics for AD

Challenges for Alzheimer's Disease Therapy: Insights from Novel Mechanisms Beyond Memory Defects

Alzheimer's disease (AD), the most common form of dementia in late life, will become even more prevalent by midcentury, constituting a major global health concern with huge implications for individuals and society. Despite scientific breakthroughs during the past decades that have expanded our knowledge on the cellular and molecular bases of AD, therapies that effectively halt disease progression are still lacking, and focused efforts are needed to address this public health challenge. Because AD is classically recognized as a disease of memory, studies have mainly focused on investigating memory-associated brain defects. However, compelling evidence has indicated that additional brain regions, not classically linked to memory, are also affected in the course of disease. In this review, we outline the current understanding of key pathophysiological mechanisms in AD and their clinical manifestation. We also highlight how considering the complex nature of AD pathogenesis, and exploring repurposed drug approaches can pave the road toward the development of novel therapeutics for AD

TNF-α mediates PKR-dependent memory impairment and brain IRS-1 inhibition induced by Alzheimer's β-Amyloid oligomers in mice and monkeys

Alzheimer's disease (AD) and type 2 diabetes appear to share similar pathogenic mechanisms. dsRNA-dependent protein kinase (PKR) underlies peripheral insulin resistance in metabolic disorders. PKR phosphorylates eukaryotic translation initiation factor 2α (eIF2α-P), and AD brains exhibit elevated phospho-PKR and eIF2α-P levels. Whether and how PKR and eIF2α-P participate in defective brain insulin signaling and cognitive impairment in AD are unknown. We report that β-amyloid oligomers, AD-associated toxins, activate PKR in a tumor necrosis factor α (TNF-α)-dependent manner, resulting in eIF2α-P, neuronal insulin receptor substrate (IRS-1) inhibition, synapse loss, and memory impairment. Brain phospho-PKR and eIF2α-P were elevated in AD animal models, including monkeys given intracerebroventricular oligomer infusions. Oligomers failed to trigger eIF2α-P and cognitive impairment in PKR(-/-) and TNFR1(-/-) mice. Bolstering insulin signaling rescued phospho-PKR and eIF2α-P. Results reveal pathogenic mechanisms shared by AD and diabetes and establish that proinflammatory signaling mediates oligomer-induced IRS-1 inhibition and PKR-dependent synapse and memory loss

Alzheimer-associated a Beta oligomers impact the central nervous system to induce peripheral metabolic deregulation

Alzheimer's disease (AD) is associated with peripheral metabolic disorders. Clinical/epidemiological data indicate increased risk of diabetes in AD patients. Here, we show that intracerebroventricular infusion of AD-associated A beta oligomers (A beta Os) in mice triggered peripheral glucose intolerance, a phenomenon further verified in two transgenic mouse models of AD. Systemically injected A beta Os failed to induce glucose intolerance, suggesting A beta Os target brain regions involved in peripheral metabolic control. Accordingly, we show that A beta Os affected hypothalamic neurons in culture, inducing eukaryotic translation initiation factor 2 alpha phosphorylation (eIF2 alpha-P). A beta Os further induced eIF2 alpha-P and activated proinflammatory IKK beta/NF-kappa B signaling in the hypothalamus of mice and macaques. A beta Os failed to trigger peripheral glucose intolerance in tumor necrosis factor-alpha (TNF-alpha) receptor 1 knockout mice. Pharmacological inhibition of brain inflammation and endoplasmic reticulum stress prevented glucose intolerance in mice, indicating that A beta Os act via a central route to affect peripheral glucose homeostasis. While the hypothalamus has been largely ignored in the AD field, our findings indicate that A beta Os affect this brain region and reveal novel shared molecular mechanisms between hypothalamic dysfunction in metabolic disorders and AD72190210CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQCOORDENAÇÃO DE APERFEIÇOAMENTO DE PESSOAL DE NÍVEL SUPERIOR - CAPESFUNDAÇÃO CARLOS CHAGAS FILHO DE AMPARO À PESQUISA DO ESTADO DO RIO DE JANEIRO - FAPERJFUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESPsem informaçãosem informaçãosem informação2012/12202-4Human Frontier Science Program; National Institute for Translational Neuroscience (INNT/Brazil); Canadian Institutes of Health Research (CIHR); Canada Research Chair

Alzheimer-associated Aβ oligomers impact the central nervous system to induce peripheral metabolic deregulation

Alzheimer's disease (AD) is associated with peripheral metabolic disorders. Clinical/epidemiological data indicate increased risk of diabetes in AD patients. Here, we show that intracerebroventricular infusion of AD-associated Aβ oligomers (AβOs) in mice triggered peripheral glucose intolerance, a phenomenon further verified in two transgenic mouse models of AD. Systemically injected AβOs failed to induce glucose intolerance, suggesting AβOs target brain regions involved in peripheral metabolic control. Accordingly, we show that AβOs affected hypothalamic neurons in culture, inducing eukaryotic translation initiation factor 2α phosphorylation (eIF2α-P). AβOs further induced eIF2α-P and activated pro-inflammatory IKKβ/NF-κB signaling in the hypothalamus of mice and macaques. AβOs failed to trigger peripheral glucose intolerance in tumor necrosis factor-α (TNF-α) receptor 1 knockout mice. Pharmacological inhibition of brain inflammation and endoplasmic reticulum stress prevented glucose intolerance in mice, indicating that AβOs act via a central route to affect peripheral glucose homeostasis. While the hypothalamus has been largely ignored in the AD field, our findings indicate that AβOs affect this brain region and reveal novel shared molecular mechanisms between hypothalamic dysfunction in metabolic disorders and AD

Amyloid-[beta] induced toxicity involves ganglioside expression and is sensitive to GM1 neuroprotective action

The effect of Ab25–35 peptide, in its fibrillar and non-fibrillar forms, on ganglioside expression in organotypic hippocampal slice cultures was investigated. Gangliosides were endogenously labeled with D-[1-C14] galactose and results showed that Ab25–35 affected ganglioside expression, depending on the peptide aggregation state, that is, fibrillar Ab25–35 caused an increase in GM3 labeling and a reduction in GD1b labeling, whereas the non-fibrillar form was able to enhance GM1 expression. Interestingly, GM1 exhibited a neuroprotective effect in this organotypic model, since pre-treatment of the hippocampal slices with GM1 10 lM was able to prevent the toxicity triggered by the fibrillar Ab25–35, when measured by propidium iodide uptake protocol. With the purpose of further investigating a possible mechanism of action, we analyzed the effect of GM1 treatment (1, 6, 12 and 24 h) upon the Ab-induced alterations on GSK3b dephosphorylation/activation state. Results demonstrated an important effect after 24-h incubation, with GM1 preventing the Ab-induced dephosphorylation (activation) of GSK3b, a signaling pathway involved in apoptosis triggering and neuronal death in models of Alzheimer’s disease. Taken together, present results provide a new and important support for ganglioside participation in development of Alzheimer’s disease experimental models and suggest a protective role for GM1 in Ab-induced toxicity. This may be useful for designing new therapeutic strategies for Alzheimer’s treatment