Alzheimer disease (AD) is the most common cause of dementia in people over 60 years old. The molecular and cellular alterations that trigger this disease are still diffuse, one of the reasons for the delay in finding an effective treatment. In the search for new targets to search for novel therapeutic avenues, clinical studies in patients who used anti-inflammatory drugs indicating a lower incidence of AD have been of value to support the neuroinflammatory hypothesis of the neurodegenerative processes and the role of innate immunity in this disease. Neuroinflammation appears to occur as a consequence of a series of damage signals, including trauma, infection, oxidative agents, redox iron, oligomers of tau and beta amyloid, etc. In this context, our theory of Neuroimmunomodulation focus on the link between neuronal damage and brain inflammatory process, mediated by the progressive activation of astrocytes and microglial cells with the consequent overproduction of proinflammatory agents. Here, we discuss about the role of microglial and astrocytic cells, the principal agents in neuroinflammation process, in the development of neurodegenerative diseases such as AD. In this context, we also evaluated the potential relevance of natural anti-inflammatory components, which include curcumin and the novel Andean Compound, as agents for AD prevention and as a coadjuvant for AD treatments.

Hyperinsulinemia as well as type II diabetes mellitus are among the risk factors for Alzheimers disease (AD). However, the molecular and cellular basis that link insulin resistance disorders and diabetes with AD are far from clear. Here, we discuss the potential molecular mechanisms that may explain the participation of these metabolic disorders in the pathogenesis of AD. The human brain uses glucose as a primary fuel; insulin secreted by the pancreas cross the bloodbrain barrier (BBB), reaching neurons and glial cells, and exerts a region-specific effect on glucose metabolism. Glucose homeostasis is critical for energy generation, neuronal maintenance, neurogenesis, neurotransmitter regulation, cell survival and synaptic plasticity. It also plays a key role in cognitive function. In an insulin resistance condition, there is a reduced sensitivity to insulin resulting in hyperinsulinemia; this condition persists for several years before becoming fullblown diabetes. Toxic levels of insulin negatively influence neuronal function and survival, and elevation of peripheral insulin concentration acutely increases its cerebrospinal fluid (CSF) concentration. Peripheral hyperinsulinemia correlates with an abnormal removal of the amyloid beta peptide (Aβ) and an increase of tau hyperphosphorylation as a result of augmented cdk5 and GSK3β activities. This leads to cellular cascades that trigger a neurodegenerative phenotype and decline in cognitive function. Chronic peripheral hyperinsulinemia results in a reduction of insulin transport across the BBB and a reduced insulin signaling in brain, altering all of insulins actions, including its anti-apoptotic effect. However, the increase in brain insulin levels resulting from its peripheral administration at optimal doses has shown a cognitionenhancing effect in patient with AD. Some drugs utilized in type II diabetes mellitus reduce cognitive impairment associated with AD. The link between insulin resistance and neurodegeneration and AD, and the possible therapeutic targets in preventing the insulin-resistance disorders are analyzed.

Evidence has been cumulated on the role of microglia cells deregulation and alterations in their interaction patterns with brain neurons, in the pathway towards neurodegeneration in Alzheimer’s disease (AD). After the failure of the amyloid hypothesis to explain AD pathogenesis, current hypotheses focus on tau self-polymerization into pathological oligomers and filaments as a major culprit for neurofibrillary degeneration. It is worth pointing out that formation of tau polymers is consistent with the clinical and neuropathological observations, and that tangles are pathognomonic of AD and related tau disorders. In this context, inflammatory processes play a major role in neuronal degeneration. On the basis of studies on microglia and neuronal cultures, together with experiments in animal models, and the clinical evidence, we postulated that a series of endogenous damage signals activate microglia cells, inducing NFĸ-β with the consequent release of cytokine mediators such as TNF-α, IL-6 and IL-1β. An overexpression of these mediators may trigger signaling cascades in neurons leading to activation of protein kinases gsk3β, cdk5, abl kinases, along with inactivation of phosphatases such as PP1, with the resulting hyperphosphorylation and self-aggregation of tau protein into neurotoxic oligomeric species.

Alzheimer´s disease (AD) and related forms of dementia are increasingly affecting the aging population throughout the world, at an alarming rate. The World Alzheimer´s Report indicates a prevalence of 46.8 million people affected by AD worldwide. As population ages, this number is projected to triple by 2050 unless effective interventions are developed and implemented. Urgent efforts are required for an early detection of this disease. The ultimate goal is the identification of viable targets for the development of molecular markers and validation of their use for early diagnosis of AD that may improve treatment and the disease outcome in patients. The diagnosis of AD has been difficult to resolve since approaches for early and accurate detection and follow-up of AD patients at the clinical level have been reported only recently. Some proposed AD biomarkers include the detection of pathophysiological processes in the brain in vivo with new imaging techniques and novel PET ligands, and the determination of pathogenic proteins in cerebrospinal fluid showing anomalous levels of hyperphosphorylated tau and low Aβ peptide. These biomarkers have been increasingly accepted by AD diagnostic criteria and are important tools for the design of clinical trials, but difficulties in accessibility to costly and invasive procedures have not been completely addressed in clinical settings. New biomarkers are currently being developed to allow determinations of multiple pathological processes including neuroinflammation, synaptic dysfunction, metabolic impairment, protein aggregation and neurodegeneration. Highly specific and sensitive blood biomarkers, using less-invasive procedures to detect AD, are derived from the discoveries of peripheric tau oligomers and amyloid variants in human plasma and platelets. We have also developed a blood tau biomarker that correlates with a cognitive decline and also with neuroimaging determinations of brain atrophy.

A cumulative number of approaches have been carried out to elucidate the pathogenesis of Alzheimer´s disease (AD). Tangle formation has been identified as a major event involved in the neurodegenerative process, due to the conversion of either soluble peptides or oligomers into insoluble filaments. Most of recent studies share in common the observation that formation of tau oligomers and the subsequent pathological filaments arrays is a critical step in AD etiopathogenesis. Oligomeric tau species appear to be neurotoxic for neuronal cells, and therefore appear as an appropriate target for the design of molecules that may control morphological and functional alterations leading to cognitive impairment. Thus, current therapeutic strategies are aimed at three major types of molecules: 1) Inhibitors of protein kinases and phosphatases that may control neuronal degeneration, 2) Methylene blue, and 3) Natural phytocomplexes and polyphenolics compounds able to either inhibit the formation of tau filaments or disaggregate them. Only a few polyphenolic molecules have emerged to prevent tau aggregation. Fulvic acid, a humic substance, has a potential activity to protect cognitive impairment. In fact, formation of paired helical filaments (PHFs) in vitro, is inhibited by fulvic acid affecting the length of fibrils and their morphology.

Pathological tau protein aggregates can be found in brain of patients with some of the neurodegenerative diseases collectively known as tauopathies, which include Alzheimers disease (AD). Since tau post-translational modifications including phosphorylations, glycosylations, truncation and the subsequent aggregation in oligomers, paired helical filaments (PHFs) and neurofibrillary tangles (NFTs), correlate with cognitive impairment and neurodegeneration in AD, a pathogenic role for tau and its modifications has been raised. Here we summarize the current status of knowledge about tau modifications under pathologic conditions and the evidence supporting neurotoxic - or neuroprotective - roles of the diverse forms of modified and aggregated tau. Finally, we analyze the structural and functional tau alterations found in different tauopathies and how these modifications are related to the pathophysiologic mechanisms of neurodegeneration.