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Strategies to enhance Alzheimer’s pathology
As already seen, EA pathogenesis is mainly based on the amyloid waterfall. However, numerous lines of research have shown that in order for neurodegeneration to be essential, the inflammation caused by the activation of glial cells, including microglia and astrocytes, which are fundamentally close to the senile plates of individuals with EA, whatthat suggests its importance in the pathogenicity of the EA.
Microglia cells are resident macrophages of the central nervous system (CNS) that are in normal conditions in a quiescent state watching the CNS. The microglia has pathogen recognition receptors (PRR), such as the TLR or the SCAVANGER, capable of recognizing molecular patterns associated with pathogens (PAMPS) and molecular patterns associated with damage (DAMPS), so in the presence of pathogens they are activatedPresenting phagocytic activity, in addition to acting as an antigen presenter.
The truth is that activated microglia plays contradictory papers in EA’s pathogenesis, since it exercises both beneficial and harmful functions. On the one hand, it provides neuroprotective factors, it can clarify the βa peptides and repair damaged tissues, but on the other hand it is neurotoxic due to the production of pro -inflammatory cytokines, chemioquins, nitric oxide induced synthase (inos) and reactive oxygen species, which canalter neuronal functions and produce cell damage.
Microglia interacts with both βa and app by specific PRRS, including CD14, CD36 and Toll-Like Receivers (TLR), which are expressed on its surface. This interaction is necessary for microglia activation, which is phenotypically and functionally diverse, since the response depends on the type, intensity and context of the stimulus. Based on these factors, a neuroprotective effect or a neurotoxic effect can be generated, since in general a moderate activation grants protective effects facilitating the elimination of βa, while an overactivation by βa or app triggers an exaggerated inflammatory response that worsens the neurodegenerative processIn the EA. Fakhoury m.
The βA peptide activates microglia through the TLR 2,4 and 9 triggering a signaling waterfall that involves MyD88 and the activation of transcription factors such as NF-κB and AP-1.
Once the microglia is activated, a pro-inflammatory waterfall is initiated that results in the release of cytotoxic molecules such as cytokines (IL-1α, IL-1β, IL-6, IL-10, IL-12, IL-16, IL-6, IL-23, TNF-α, TGF-β), chemiocins, proteases, acute phase proteins and complement proteins that will also cause astrocyte chemotaxis around the plates. These pro-inflammatory elements trigger a waterfall of events, such as oxidative stress, demialination and apoptosis, which will finally culminate in neurodegeneration and cognitive decline. In addition, activated microglia releases high glutamate levels, which induces excitotoxicity, thus contributing to neurodegeneration.
It has been seen that there is a high expression of TLR2 and MYD88 in the hippocampus and the cortex of patients with EA , being myd88 an adapter protein that is essential for inflammation to take place and thus accentuates the pathology of Alzheimer’s-
Taking into account this, a way to increase neurodegeneration through microglyBs in the EA would be either to increase the expression of the TLR2 and MYD88, so that in the presence of BA there is an overactivation that triggers an inflammatory response that causes neurodegeneration, either overexpress and overact the transcription factor NF-κB, so that there is a greater waterfall of pro-inflammatory cytokines.
On the other hand, a more general mechanism could be used, how to design a peptide that causes a microglia overactivation, thus triggering neurotoxicity.
Recapitulating, the active βa peptide to microglia, which in turn recruit astrocytes, which are the most abundant glial cells and that in physiological conditions fulfillThe formation and maintenance of the hematoencephalic barrier, produce neurotrophic and neuroprotective factors or how to participate in the repair processes within the CNS.
Astrocytes are activated or by βa peptides or in response to damage, after which they participate in the secretion of inflammatory cytokines including IL-1, IL-6, and TNF-α, thus promoting the neurodegenerative process in EA.
Astrocytes express a series of receptors through which they interact with βa, such as RAGE, LRP or SCAVENGER receptors. On the other hand, βA aggregates stimulate the production of chemotactic molecules such as monocyte chemotive protein (MCP-1) that mediates the recruitment of astrocytes to the site of the lesion. In addition, BA activates in astrocytes, as in microglia, the Astroglial-Kappa B (NFᴋB) nuclear factor is enhanced by the production of inflammatory mediators. Taking all this into account, the unleashed inflammation could be enhanced and therefore the neurodegeneration caused, by means. It is worth mentioning that astrocytes can produce BA through TGF-β1 alone or IFN-γ in combination with TNF-α or IL-1β, so a way to aggravate the disease would be to signal astrocytes with these factors so that there are.
In addition, astrocytes release different trophic factors that can or be beneficial or harmful in the EA, which can be used as a strategy to accentuate the damage. For example, it has been seen that GNFD improves neuronal function and cognitive development, while NGF overexpression by astrocytes derives in neurotoxicity and degenerative loss of hippocampus neurons. These trophic factors can therefore be used as a strategy to aggravate the neurodegeneration of EA, on the one hand, inhibiting the GNFD and on the other hand overexpressing the NGF.
In short, there are many strategies related to the inflammation of the glial cells by which Alzheimer’s disease can be intensified, since in the development of neurodegeneration not only the BA peptides are involved, but the inflammatory mediators, in addition to generating effectsNeurotoxic, they also stimulate app processing overexpressing the enzyme Beta Secreta 1, thus establishing a vicious circle where they are activated by glial cells, which produce inflammatory mediators that in turn stimulate the production of BA that thus trigger a waterfall of events.