The Multifactorial Etiopathogenesis of Alzheimer's Disease: Neuroinflammation as the Major Contributor.

Alzheimer's disease (AD) is the most common form of dementia in the elderly. AD is a multifactorial disease, affected by several factors including amyloid-ß42 oligomers, self-assembled tau, microbiota molecules, etc. However, inflammatory components are critical to trigger AD. Neuroinflammatory pathology links glial activation by "damage signals" with tau hyperphosphorylation, as explained by the Neuroimmunomodulation Theory, discovered by the ICC laboratory. This theory elucidates the onset and progression of several degenerative diseases and concept of "multitarget" therapy. These studies led to the rationale to identify inflammatory targets for the action of bioactive molecules or drugs against AD.

Monoamines and their Derivatives on GPCRs: Potential Therapy for Alzheimer's Disease.

Albeit cholinergic depletion remains the key event in Alzheimer's Disease (AD), recent information describes stronger links between monoamines (trace amines, catecholamines, histamine, serotonin, and melatonin) and AD than those known in the past century. Therefore, new drug design strategies focus efforts to translate the scope on these topics and to offer new drugs which can be applied as therapeutic tools in AD. In the present work, we reviewed the state-of-art regarding genetic, neuropathology and neurochemistry of AD involving monoamine systems. Then, we compiled the effects of monoamines found in the brain of mammals as well as the reported effects of their derivatives and some structure-activity relationships. Recent derivatives have triggered exciting effects and pharmacokinetic properties in both murine models and humans. In some cases, the mechanism of action is clear, essentially through the interaction on G-protein-coupled receptors as revised in this manuscript. Additional mechanisms are inhibition of enzymes for their biotransformation, regulation of free-radicals in the central nervous system and others for the effects on Tau phosphorylation or amyloid-beta accumulation. All these data make the monoamines and their derivatives attractive potential elements for AD therapy.

Terapia antiamiloide: uma nova estratégia para tratamento da doença de Alzheimer / Antiamyloid therapy: a new strategy for treating Alzheimer's disease

A doença de Alzheimer é a patologia neurodegenerativa mais frequente associada à idade, cujas manifestações cognitivas e neuropsiquiátricas resultam em deficiência progressiva e incapacitação. Existem vários tipos de terapias farmacológicas que visam melhorar a qualidade de vida do paciente afetado por esta patologia. Muitos medicamentos são usados há muito tempo para o tratamento da doença, sendo os inibidores da colinesterase as drogas de primeira escolha para o tratamento, mas nenhum deles regride a progressão da doença de Alzheimer. Novos estudos têm sido realizados, com o objetivo de procurar um novo medicamento que seja capaz de ajudar em sua regressão. Ainda, novos tratamentos, como a terapêutica antiamiloide, são opções que estão sendo observados para uma melhor terapêutica. Estes tratamentos são descritos nesta revisão, que teve como objeitvo analisar os benefícios do tratamento da doença de Alzheimer, por meio da terapêutica antiamiloide, em que se enquadra a imunoterapia.(AU)

Alzheimer's disease is the most common neurodegenerative disorder associated with age, whose cognitive and neuropsychiatric manifestations result in progressive disability and incapacitation. There are several types of pharmacological therapies aimed at improving the patient's quality of life affected by this disease. Many medications have long been used for the treatment of the disease, with cholinesterase inhibitors being the drugs of first choice for the treatment but none of them regress the progression of Alzheimer's disease. Further studies have been made to search a new drug able to assist in the regression of the disease. In addition, new therapies such as the anti-amyloid one are options that are being observed to improve treatment. These therapies are described in this review, which aims at analyzing the benefits of anti-amyloid therapy for Alzheimer's disease, in which immunotherapy is included.(AU)

Metabolic Syndrome Exacerbates the Recognition Memory Impairment and Oxidative-Inflammatory Response in Rats with an Intrahippocampal Injection of Amyloid Beta 1-42.

An important worldwide health problem as the result of current lifestyle is metabolic syndrome (MS). It has been shown that MS induced by a high-calorie diet (HCD) in rats produces cognitive deterioration in the novel object recognition test (NORt) and decreases synaptic connections and dendritic order in the hippocampus and temporal cortex. However, it is unknown whether MS induced by an HCD participates in the cognitive process observed with the injection of Aß1-42 into the hippocampus of rats as a model of Alzheimer disease (AD). The induction of MS in rats produces a deterioration in NORt; however, rats with MS injected with Aß1-42 show a major deterioration in the cognitive process. This event could be explained by the increment in the oxidative stress in both cases studied (MS and Aß1-42): together, the hippocampus and temporal cortex produce an enhancer effect. In the same way, we observed an increment in interleukin-1ß, TNF-α, and GFAP, indicative of exacerbated inflammatory processes by the combination of MS and Aß1-42. We can conclude that MS might play a key role in the apparition and development of cognitive disorders, including AD. We propose that metabolic theory is important to explain the apparition of cognitive diseases.

[One hundred years of Alzheimer's disease: immunotherapy a hope?]. / Cien años de la enfermedad de Alzheimer: La inmunoterapia ¿una esperanza?

In 1906 Alois Alzheimer, described the cerebral lesions characteristic of the disorder that received his name: senile plaques and neurofibrillary tangles. Alzheimer's disease (AD) is now, 100 years after, the most prevalent form of dementia in the world. The longer life expectancy and aging of the population renders it as a serious public health problem of the future. Urgent methods of diagnosis and treatment are required, since the definitive diagnosis of AD continues to be neuropathologic. In the last 30 years several drugs have been approved to retard the progression of the disease; however, there are still no curative or preventive treatments. Although still in experimentation, the visualization of amyloid deposition by positron emission tomography or magnetic resonance imaging will allow in vivo diagnosis of AD. In addition, experiments with the amyloid vaccine are still ongoing, and very recent data suggest that intravenous gammaglobulins may be beneficial and safe for the treatment of AD.

Cien años de la enfermedad de Alzheimer: La inmunoterapia ¿una esperanza? / One hundred years of Alzheimer's disease: Immunotherapy a hope?

In 1906 Alois Alzheimer, described the cerebral lesions characteristic of the disorder that received his name: senile plaques and neurofibrillary tangles. Alzheimer's disease (AD) is now, 100 years after, the most prevalent form of dementia in the world. The longer life expectancy and aging of the population renders it as a serious public health problem of the future. Urgent methods of diagnosis and treatment are required, since the definitive diagnosis of AD continues to be neuropathologic. In the last 30 years several drugs have been approved to retard the progression of the disease; however, there are still no curative or preventive treatments. Although still in experimentation, the visualization of amyloid deposition by positron emission tomography or magnetic resonance imaging will allow in vivo diagnosis of AD. In addition, experiments with the amyloid vaccine are still ongoing, and very recent data suggest that intravenous gammaglobulins may be beneficial and safe for the treatment of AD.

Beta-sheet breaker peptide prevents Abeta-induced spatial memory impairments with partial reduction of amyloid deposits.

Current evidence supports the notion that beta-amyloid deposits or Abeta intermediates may be responsible for the pathogenesis in Alzheimer's disease (AD) patients. In the present work, we have assessed the neuroprotective effect of the chronic intraperitoneal administration of a five-amino-acid beta-sheet breaker peptide (iAbeta5p) on the rat behavioral deficit induced by the intrahippocampal Abeta-fibrils injection. At 1 month after the injection, animals showed a partial reduction of the amyloid deposits formed and a decreased astrocytic response around the injection site. More importantly, we report that following the iAbeta5p treatment, hippocampal-dependent spatial learning paradigms, including the standard Morris water maze and a working memory analysis, showed a significant prevention from impairments induced by Abeta deposits in the dorsal hippocampus. Thus, it is possible that a noninvasive treatment such as the one presented here with beta-sheet breaker peptides may be used as a potential therapy for AD patients.