Inflamación crónica y Alzheimer

Deciphering the mechanism underlying late-onset Alzheimer disease

by Dimitrije Krstic & Irene Knuesel  

El trabajo que he escogido tiene que ver con el desarrollo del Alzheimer, (AD)enfermedad degenerativa del sistema nervioso central caracterizada por la formación de placas amiloides. Es muy interesante por arrojar luz sobre cómo se desencadena dicho proceso en relación a distintos factores celulares. 

Pese a los ingentes esfuerzos investigadores dedicados a comprender los complejos mecanismos moleculares asociados con el origen y desarrollo del Alzheimer  todos los ensayos clínicos recientes han resultado fallidos. Según los autores del presente trabajo publicado en "Nature"  mucho tiene que ver a que se da por cierto que los mecanismos moleculares que desencadenan la enfermedad, vinculada a ciertos genes, (se sabe con seguridad que existen genes que favorecen el desarrollo de AD) son idénticos a los que ocurren cuando dicha dolencia se presenta en edad muy avanzada. Aquí se describe la importancia de los procesos inflamatorios crónicos que, estudiados en un modelo experimental, consiguen reproducir la formación placas amiloides y los cambios degenerativos. En resúmen se trata de desentrañar detalles de qué mata a las células nerviosas y cómo ocurre. Al menos en el presente estudio se apunta a la inflamación crónica como posible desencadenante a nivel molecular.

Review criteria (Para aquellos lectores que deseen hacer una revisión del asunto incluyo los criterios de búsqueda que siguieron los autores. Les serán muy útiles)

Full-text, English-language articles were included in the search, without restrictions on publication date. We searched the MEDLINE and PubMed databases, and used the Google search engine, for terms including: “Alzheimer disease”, “inflammation”, “neuroinflammation, “ageing”, “GWAS”, “infection”, “cognition”, “dementia”, “tau hyperphosphorylation”, “amyloid precursor protein”, “axonal transport”, “cytoskeleton abnormalities”, “oxidative stress”, “lysosomes”, “autophagy”, “protein degradation”, “microglia”, “senile plaques”, “neurofibrillary tangle”, “neurodegeneration”, and “caspases”. Reference lists of selected articles were searched to identify further references. Our search for observations in AD was based on selected reviews on clinical and pathophysiological aspects of AD, and on PubMed searches using the above terms in combination with: “oldest-old”, “nonagenarians”, “without/no dementia”, “high pathology”, AND the filter “species: human”.

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AbstractAbstract

"Despite tremendous investments in understanding the complex molecular mechanisms underlying Alzheimer disease (AD), recent clinical trials have failed to show efficacy. A potential problem underlying these failures is the assumption that the molecular mechanism mediating the genetically determined form of the disease is identical to the one resulting in late-onset AD. Here, we integrate experimental evidence outside the 'spotlight' of the genetic drivers of amyloid-β (Aβ) generation published during the past two decades, and present a mechanistic explanation for the pathophysiological changes that characterize late-onset AD. We propose that chronic inflammatory conditions cause dysregulation of mechanisms to clear misfolded or damaged neuronal proteins that accumulate with age, and concomitantly lead to tau-associated impairments of axonal integrity and transport. Such changes have several neuropathological consequences: focal accumulation of mitochondria, resulting in metabolic impairments; induction of axonal swelling and leakage, followed by destabilization of synaptic contacts; deposition of amyloid precursor protein in swollen neurites, and generation of aggregation-prone peptides; further tau hyperphosphorylation, ultimately resulting in neurofibrillary tangle formation and neuronal death. The proposed sequence of events provides a link between Aβ and tau-related neuropathology, and underscores the concept that degenerating neurites represent a cause rather than a consequence of Aβ accumulation in late-onset AD".

Key points

• Despite tremendous investments in basic and clinical research, no cure or preventive treatment for Alzheimer disease (AD) exists (Para el AD no hay tratamiento preventivo o cura)
• A re-evaluation of the current view of the mechanisms underlying late-onset AD pathology is a prerequisite for future translational approaches (La re-evaluación de los mecanismos que desencadenan el (AD) en la edad avanzada es un prerequisito para futuros desarrollos)
• Inflammatory processes are strongly correlated with AD onset and progression in humans, and could have a pivotal role in disease aetiology (Los procesos inflamatorios se encuentran marcadamente correlacionados con el inicio y desarrollo de AD en humanos y tienen una función esencial en la etiología de la enfermedad)
• Chronic inflammation coupled with neuronal ageing induces cellular stress and concomitant impairments in basic neuronal functions (La inflamación crónica asociada con el envejecimiento neuronal provoca estres y el concomitante fallo en las funciones celulares básicas)
• Inflammation-induced hyperphosphorylation and missorting of tau might represent one of the earliest neuropathological changes in late-onset AD (La inflamación desencadena cambios como por ejemplo la hiperfosforilación)
• Molecular changes underlying late-onset AD involve impairments in cytoskeleton stability and axonal transport, which could trigger axonal degeneration and formation of senile plaques and neurofibrillary tangles, resulting in neuronal death (Los cambios moleculares que se producen durante el desarrollo de (AD) en edad avanzada conllevan disfunciones del citoesqueleto, del transporte axonal y pueden favorecer la degeneración del axon y la formación de placas seniles, además de otros cambios en las neurofibrillas. Los cambios estructurales conducen a la muerte de las neuronas)

The inflammation hypothesis of late-onset Alzheimer disease.

a | During healthy ageing, a conserved protein extrusion mechanism compensates for ageing-dependent failures in protein clearance and degradation (step 1). Cellular stress to ageing neurons accelerates formation of varicosities and their extrusion into the extracellular matrix, where they are phagocytosed by surrounding glia (step 2). If aged neurons experience chronic inflammation, tau becomes hyperphosphorylated and is missorted to somatodendritic compartments, which impairs axonal transport (steps 2 and 3). 
b | Consequently, stress-induced APP accumulates in axonal compartments and in larger swellings (step 3). Chronic inflammation also 'primes' microglia to subsequent immune challenges (step 3). Blockade of axonal transport leads to synaptic destabilization or loss, and is accompanied by formation of PHFs in neurites and membrane leakage at axonal swellings (step 4). Axonal leakage exposes cellular proteins to lysosomal proteinases, promoting formation of neurotoxic peptides. Hyperreactive microglia cannot properly remove dystrophic neurites, and create a toxic proinflammatory environment that affects surrounding neurons. Senile amyloid-β plaques begin to form (step 5). In response to neuritic degeneration, caspase activation triggers formation of neurofibrillary tangles (step 6). Imbalances in excitatory–inhibitory neurotransmission and the neurotoxic proinflammatory environment initiate pathology in interconnected brain areas. Abbreviations: APP, amyloid precursor protein; PHF, paired helical filament.