engleski

Personalized treatment of Alzheimer's disease based on estimated activators of amyloid-β deposition

The limited development of drugs for Alzheimer’s disease (AD) is mainly caused by an incomplete characterization of the basic pathologic mechanisms due to significant clinical, biological, and genetical complexity. The concept of personalized medicine aims to optimize effectiveness of more accurate diagnosis, disease prevention, and treatment strategies by considering an individual’s specific makeup of biomarker, phenotypic, and psychosocial characteristics. Based on the fact that amyloid β (Aβ) monomers can form oligomers that are cleared more slowly from the brain’s interstitial space or can aggregate to form insoluble amyloid plaques, the process of excessive processing of amyloid precursor protein (APP) in neurons by β- and γ- secretases is still the key target to treat AD. However, this classic amyloid cascade hypothesis does not take into account beneficial roles that Aβ plays in the brain, such as protecting from infections, sealing leaks in the blood-brain barrier (BBB) thus preventing stroke, promoting recovery from traumatic brain injury (TBI), regulating synaptic function, and, by intercepting oncogenic viruses, contributing even to tumor suppression. These over 500 million-year old positive roles of Aβ make it to the surface either as the ARIA (Amyloid-Related Imaging Abnormalities) syndrome or as adverse outcomes, especially in clinical trials that have attempted to deplete Aβ in order to treat AD. The best current understanding suggests that AD is a disorder triggered by impairment of APP metabolism, which then progresses primarily through microglial activation and tau pathology rather than through simple Aβ accumulation. Following microglial uptake of hyperphosphorylated and aggregated tau protein seeds, they are sorted to lysosomes, which, in turn, release inflammasome-activating cathepsins. During my talk I will thus argue that more favorable clinical outcome might be achieved by treating the known triggers of Aβ deposition prior to targeting Aβ production. This would involve screening subjects for potential causes of BBB leakage (TBI, diabetes, vascular hypertension) as well as for latent bacterial or viral infection. In these persons, anti-inflammatory treatments should slow down the rate of Aβ deposition and improve cognitive status. Once these known activators of Aβ deposition have been addressed, subsequent anti-Aβ active or passive immuno- and other therapies are expected to be associated with fewer instances of ARIA or neuroinflammation. Several large epidemiological and observational studies already reported that anti-inflammatory treatments shown to be protective against developing AD, and demonstrated as much as a 50% reduction in the risk for developing AD in patients who are long- term nonsteroidal anti-inflammatory drug (NSAID) users. However, a systematic review and meta- analysis of seven human trials of NSAIDS in late- onset AD showed variable outcomes with no convincing evidence of benefit, most likely due to the fact that anti-inflammatory treatment was given non-selectively to patients with clinical diagnosis of AD in advanced stage of dementia.

Alzheimer's disease ; animal model ; cognitive impairment ; entorhinal cortex ; tauopathy ; tau proteins

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