Alzheimer's Disease: A Silent Pandemic - A Systematic Review on the Situation and Patent Landscape of the Diagnosis.

BACKGROUND: Alzheimer's disease (AD) is characterized by cognitive impairment, tau protein deposits, and amyloid beta plaques. AD impacted 44 million people in 2016, and it is estimated to affect 100 million people by 2050. AD is disregarded as a pandemic compared with other diseases. To date, there is no effective treatment or diagnosis. OBJECTIVE: We aimed to discuss the current tools used to diagnose COVID-19, point out their potential to be adapted for AD diagnosis, and review the landscape of existing patents in the AD field and future perspectives for AD diagnosis. METHODS: We carried out a scientific screening following a research strategy in PubMed; Web of Science; the Derwent Innovation Index; the KCI-Korean Journal Database; Sci- ELO; the Russian Science Citation index; and the CDerwent, EDerwent, and MDerwent index databases. RESULTS: A total of 326 from 6,446 articles about AD and 376 from 4,595 articles about COVID-19 were analyzed. Of these, AD patents were focused on biomarkers and neuroimaging with no accurate, validated diagnostic methods, and only 7% of kit development patents were found. In comparison, COVID-19 patents were 60% about kit development for diagnosis; they are highly accurate and are now commercialized. CONCLUSION: AD is still neglected and not recognized as a pandemic that affects the people and economies of all nations. There is a gap in the development of AD diagnostic tools that could be filled if the interest and effort that has been invested in tackling the COVID-19 emergency could also be applied for innovation.

Structural and Functional Analysis of Female Sex Hormones against SARS-CoV-2 Cell Entry.

Emerging evidence suggests that males are more susceptible to severe infection by the SARS-CoV-2 virus than females. A variety of mechanisms may underlie the observed gender-related disparities including differences in sex hormones. However, the precise mechanisms by which female sex hormones may provide protection against SARS-CoV-2 infectivity remains unknown. Here we report new insights into the molecular basis of the interactions between the SARS-CoV-2 spike (S) protein and the human ACE2 receptor. We further report that glycosylation of the ACE2 receptor enhances SARS-CoV-2 infectivity. Importantly, estrogens can disrupt glycan-glycan interactions and glycan-protein interactions between the human ACE2 and the SARS-CoV-2 thereby blocking its entry into cells. In a mouse model of COVID-19, estrogens reduced ACE2 glycosylation and thereby alveolar uptake of the SARS-CoV-2 spike protein. These results shed light on a putative mechanism whereby female sex hormones may provide protection from developing severe infection and could inform the development of future therapies against COVID-19.

Vascular smooth muscle cell dysfunction contribute to neuroinflammation and Tau hyperphosphorylation in Alzheimer disease.

Despite the emerging evidence implying early vascular contributions to neurodegenerative syndromes, the role of vascular smooth muscle cells (VSMCs) in the pathogenesis of Alzheimer disease (AD) is still not well understood. Herein, we show that VSMCs in brains of patients with AD and animal models of the disease are deficient in multiple VSMC contractile markers which correlated with Tau accumulation in brain arterioles. Ex vivo and in vitro experiments demonstrated that VSMCs undergo dramatic phenotypic transitions under AD-like conditions, adopting pro-inflammatory phenotypes. Notably, these changes coincided with Tau hyperphosphorylation at residues Y18, T205, and S262. We also observed that VSMC dysfunction occurred in an age-dependent manner and that expression of Sm22α protein was inversely correlated with CD68 and Tau expression in brain arterioles of the 3xTg-AD and 5xFAD mice. Together, these findings further support the contribution of dysfunctional VSMCs in AD pathogenesis and nominate VSMCs as a potential therapeutic target in AD.

Diagnosis of Alzheimer's Disease in Developed and Developing Countries: Systematic Review and Meta-Analysis of Diagnostic Test Accuracy.

BACKGROUND: The present systematic review and meta-analysis of diagnostic test accuracy summarizes the last three decades in advances on diagnosis of Alzheimer's disease (AD) in developed and developing countries. OBJECTIVE: To determine the accuracy of biomarkers in diagnostic tools in AD, for example, cerebrospinal fluid, positron emission tomography (PET), and magnetic resonance imaging (MRI), etc. METHODS: The authors searched PubMed for published studies from 1990 to April 2020 on AD diagnostic biomarkers. 84 published studies were pooled and analyzed in this meta-analysis and diagnostic accuracy was compared by summary receiver operating characteristic statistics. RESULTS: Overall, 84 studies met the criteria and were included in a meta-analysis. For EEG, the sensitivity ranged from 67 to 98%, with a median of 80%, 95% CI [75, 91], tau-PET diagnosis sensitivity ranged from 76 to 97%, with a median of 94%, 95% CI [76, 97]; and MRI sensitivity ranged from 41 to 99%, with a median of 84%, 95% CI [81, 87]. Our results showed that tau-PET diagnosis had higher performance as compared to other diagnostic methods in this meta-analysis. CONCLUSION: Our findings showed an important discrepancy in diagnostic data for AD between developed and developing countries, which can impact global prevalence estimation and management of AD. Also, our analysis found a better performance for the tau-PET diagnostic over other methods to diagnose AD patients, but the expense of tau-PET scan seems to be the limiting factor in the diagnosis of AD in developing countries such as those found in Asia, Africa, and Latin America.

Liposomes Coloaded with Elacridar and Tariquidar To Modulate the P-Glycoprotein at the Blood-Brain Barrier.

This study prepared three liposomal formulations coloaded with elacridar and tariquidar to overcome the P-glycoprotein-mediated efflux at the blood-brain barrier. Their pharmacokinetics, brain distribution, and impact on the model P-glycoprotein substrate, loperamide, were compared to those for the coadministration of free elacridar plus free tariquidar. After intravenous administration in rats, elacridar and tariquidar in conventional liposomes were rapidly cleared from the bloodstream. Their low levels in the brain did not improve the loperamide brain distribution. Although elacridar and tariquidar in PEGylated liposomes exhibited 2.6 and 1.9 longer half-lives than free elacridar and free tariquidar, respectively, neither their Kp for the brain nor the loperamide brain distribution was improved. However, the conjugation of OX26 F(ab')2 fragments to PEGylated liposomes increased the Kps for the brain of elacridar and tariquidar by 1.4- and 2.1-fold, respectively, in comparison to both free P-gp modulators. Consequently, the Kp for the brain of loperamide increased by 2.7-fold. Moreover, the plasma pharmacokinetic parameters and liver distribution of loperamide were not modified by the PEGylated OX26 F(ab')2 immunoliposomes. Thus, this formulation represents a promising tool for modulating the P-glycoprotein-mediated efflux at the blood-brain barrier and could improve the brain uptake of any P-glycoprotein substrate that is intended to treat central nervous system diseases.

Delivery of P-glycoprotein substrates using chemosensitizers and nanotechnology for selective and efficient therapeutic outcomes.

As a result of its broad substrate specificity and critical localization in excretory and barrier function tissues, P-glycoprotein (P-gp) plays major roles in the pharmacokinetics, safety and efficacy profiles of numerous drugs. P-gp is often responsible for the failure of many chemical treatments against cancer, immunosuppressive, infectious and neurodegenerative diseases. Among the therapeutic approaches to circumvent P-gp function, advances in the design of new chemical P-gp modulators to interact specifically with P-gp have yielded few clinical successful reports. Members of a class of components that were initially developed as surface active agents showed promising results with regard to the modulation of P-gp. These components include surfactants and amphiphilic co-polymers. Alternatively, colloidal systems were developed to facilitate drug uptake in resistant cells. This approach is based on the encapsulation of drugs, which masks them from the biological environment and prevents their transport by P-gp using the surfactants released from the nanocarrier. Likewise, a novel and synergistic strategy is currently being explored and involves nanocarrier-mediated transport and controlled release of both P-gp substrates and P-gp modulators. In this review, we discuss recent results obtained by direct modulation with chemosensitizers and the available nanotechnology to modulate P-gp function. In this manuscript, we also discuss unexplored pathways for future therapies.