Alzheimer's Disease: Characterization, Evolution and Implications of the Neuroinflammatory Process

Abstract

Alzhei er's Disease: Characterizatio , Evolution and Implications of the Neuroinflammatory ProcessAbstract: álzhei e 'sàDiseaseà áD àisàaà eu odege e ativeàdisease characterized by a progressive memory loss and severe cognition decline, associated to degradation of cholinergic neurons in many areas of central nervous system (CNS), with a dramatic reduction in neurotransmitters, specially acetylcholine. The illness progression is also accompanied by behavior changes, leading to individual incapacity and depression, and evolving to dementia and death. AD is related to cerebral aging and located loss of neurons, mainly at hippocampus and basal pro-encephalic tissue. Pathohystologically, AD is characterized by extracellular deposits of senile plaques formed by insoluble fragments of amyloid protein precursor (A) and intracellular neurofibrillary tangles in the brain, constituted by fragments of hyperphosphorylated TAU protein, with a massive loss in neurons. Despite typical behavior aspects of AD installation, recent studies, especially from the last decade, have evidenced the occurrence of a complex inflammatory process in the neuronal tissue. The relevancy of neuroinflammation in the installation, progression and severity of AD, as well as the mechanisms of immune system activation and key cells in the initial shot of inflammatory cascade in CNS, as microglia and astrocytes, have been demonstrated by important reviews in the literature. Activation of microglia can lead to recruitment of astrocytes that increase the inflammatory response to the extracellular A deposits. This neuroinflammatory component of AD is additionally characterized by a local acute phase response mediated by cytokines, complement cascade activation and induction of an enzymatic inflammatory system, as induced NO synthase (iNOS) and generation of cyclooxygenase 2 (COX-2). Then, astrocytes participate of the degradation and remotion of A, acting as a protective barrier between A deposits and neurons. The multifactorial character of the inflammatory response is characterized by the occurrence of a wide diversity of pro-and anti-inflammatory mediators, some of them being responsible for promotion of neurodegenerative mechanisms, while others could limit the advance of inflammation or exert benefit neurotrophic effects. Therefore, it includes not only a single mediator, but a set of inflammatory agents that would determine the prevalence of benefic or deletery effects during AD progression.Keywords: álzhei e 'sàDisease;àNeu odege e atio ;àNeu oi fla atio . 287Rev. Virtual Quim. |Vol 3| |No. 4| |286-306| ResumoA Doença de Alzheimer (DA) é uma doença neurodegenerativa, caracterizada pela diminuição progressiva da memória e declínio severo da cognição, associados com a degradação de neurônios colinérgicos em muitas áreas do Sistema Nervoso Central (SNC), acompanhada de dramática redução de neurotransmissores, entre os quais a acetilcolina (ACh) é o mais importante. A evolução da doença é acompanhada de alterações comportamentais, que evoluem à in...

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“…Taking AD and PD as representative multifactorial diseases, despite these pathologies being distinct, they retain common characteristics such as a series of biochemical and physiological cascade events directly or indirectly associated with essential oxidative stress and inflammatory process. [95][96][97][99][100][101][102][106][107][108][109][110][111][112] Although the pharmaceutical industry aggressively markets anticholinergic drugs for the treatment of AD, these drugs have shown only marginal and transient effects, with no curative properties and only a moderate ability to restrain neurodegeneration progress. In spite of substantial investments made by the industry in search of new drugs, the truth is that progress toward innovative, small-molecule therapies for neurodegenerative diseases has been very modest.…”

“…In such pathologies, a multitude of physiological changes are present, including aberrant protein folding, protein degradation pathways, mitochondrial dysfunction, imbalanced energy production, compromised axonal transport processes, uncontrolled production of oxygen and nitrogen radical species, inflammation signaling, and ultimately induced cell death. 102,108,109,[118][119][120] In a non-physiological condition, abnormal accumulation senile plaques constituted by aggregates of toxic insoluble Aβ oligomers is due to an imbalance between the levels of Aβ production and clearance. Consequently, Aβ oligomers are overproduced and lead to synaptic damage by forming pore-like structures with channel activity, which can modify glutamate receptors and culminate in excitotoxicity.…”

“…122 The literature is rich in data supporting that inflammation around senile plaques destroys neighboring neurons, as well as intracellular neurofibrils, and is responsible for oxidative stress with an increase of radical species that in turn, modify the intracellular environment contributing for neuroinflammation. 108,114 Chronic inflammation is related to the activation of microglia, the most abundant of the resident immune cells in the brain, as a consequence of an injury to the brain tissue. Once activated, microglia produce pro-inflammatory and neurotoxic factors including cytokines such as TNF-α, interleukin-1 beta (IL-1β), IL-6, and free radicals (eg, NO, superoxide), which contribute to neuron damage, exacerbate tau pathology and contribute for chronic inflammation and the progression of neurodegeneration.…”

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“…Due to a not yet clearly understood dysfunction, enzymes such as βand γ-secretases can cleave the amyloid precursor protein (APP), generating Aβ 40 and Aβ 42 peptides that have a high aggregation capacity, producing insoluble protofibrils, responsible for the inflammatory process, among other pathological effects. Recent studies suggest that Aβ oligomers diffuse into the brain parenchyma and alter synaptic function, with selective neuronal loss in the cortex and hippocampus, regions characteristically affected in AD [5][6][7]. Among the mechanisms of neurotoxicity mediated by Aβ peptides, the formation of reactive oxygen species (ROS) and oxidative stress (OS) contribute to neuronal death.…”

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“…Histopathological studies show senile plaques formed by fragments of insoluble β-amyloid peptide and intracellular neurofibrillary tangles, which may be formed by disruption of the microtubule cytoskeleton, due to hyperphosphorylation of TAU protein, accompanied by massive loss of neurons. [ 4 ]…”