Phospholipids and Alzheimer’s disease: alterations, mechanisms and potential biomarkers

Brain is one of the richest organs in lipid content. Phospholipids (glycerophospholipids and sphingolipids) are important building blocks of cell membranes, which provide an optimal environment for protein interactions, trafficking and function. Because of that, alterations in their cellular levels could lead to different pathogenic processes in the brain, such as in Alzheimer's disease (AD), the most common type of dementia among older populations. There is increasing evidence that phospholipid changes occur during pathogenic processes in AD. It is known that lipids are tightly connected with metabolism of the Amyloid Precursor Protein (APP), which produces Amyloid-beta peptide (Aβ), the main component of senile plaques, which represent the main pathological hallmark of AD. However, the mechanism(s) of the lipid-effect on Aβ metabolism and AD pathogenesis is still not completely understood. This review summarizes the current knowledge on phospholipid changes occurring during normal aging and discusses phospholipid changes in the human brain associated with different stages of AD, as well changes in the cerebrospinal fluid and blood/plasma, which are interesting potential biomarkers for AD diagnosis and disease monitoring. At the end, we have discussed future perspectives of phospholipid changes as potential biomarkers and as targets for development of novel treatment strategies against AD

Hybrid Stem Intervention as New Post-Pandemic Approach to Motivate Students to Stem

There has long been a struggle over how to increase student interest in careers in STEM and meet the labour market’s need for specialised knowledge and skills. The long-standing debate at the EU level about the role of formal, informal, and non-formal education in meeting these challenges has not yet reached a clear conclusion. In the last decade, there has been a significant increase in the number of STEM programmes offered by various non-governmental organisations in Croatia. These interventions are often localised and have limited social impact, but there is a strong willingness to create an environment for their greater inclusion in the formal education system, triggered by comprehensive curriculum reform in Croatia. Motivation, especially intrinsic motivation, is a crucial driving force in our lives. In our pilot study, conducted with 6th grade elementary students, we aimed to explore the extent to which STEM interventions encourage students to learn more about the topic and whether it is possible to incorporate lessons learned from the pandemic into the design of future interventions. Our results show that there is no significant difference in student motivation after a 45-minute whole-class interactive intervention between face-to-face and virtual delivery. Although the intervention was entertaining, students perceived the science as interesting and useful rather than entertaining. Considering that students have positive attitudes toward Nature as a school subject, an early intervention with students at this age could be useful in maintaining their interest and preventing a decline in interest later in life. This finding is particularly important in the context of the transformation of the Croatian elementary school system into a “whole-day school”, which provides room for incorporating this type of intervention into a regular school system

Alzheimer’s disease: from molecular mechanism to early diagnosis

Alzheimerova bolest (AB) najčešći je oblik demencije. Iako je prošlo već sto godina od otkrića bolesti kao i otkrića glavnih patoloških lezija u mozgu bolesnika s AB, senilnih plakova i neurofi brilarnih snopića, još uvijek ne postoji primjerena terapija koja bi liječila bolest, usporila njenu progresiju ili spriječila njezin nastanak. S obzirom na to da promijenjen metabolizam prekursora proteina amiloid-β (APP) i promijenjena razina pepti da amiloid-β (Aβ) predstavljaju glavni uzrok nastanka Alzheimerove bolesti , razumijevanje njihovog mehanizma nastanka i razgradnje važno je za razvoj novih oblika liječenja ove bolesti . Razvoj novih dijagnosti čkih metoda koje će omogućiti rano i točno otkrivanje AB stoga je izuzetno važan. Smatra se da će razvoj bilo kojeg oblika intervencije AB imati najznačajniji učinak u najranijoj fazi bolesti kada promjene u mozgu nisu još tako značajne. Analiza razine triju proteina u likvoru (Aβ42, ukupnog tau i fosforiliranog oblika proteina tau) za sada je dala najbolje rezultate te je pokazala da se ovim testom mogu diferencijalno dijagnosti cirati osobe s AB, kao i nedementne osobe te osobe s blagim kogniti vnim poremećajem koje će u budućnosti napredovati u AB, stoga je cilj istraživanja biomarkera utvrditi promjene koje će otkriti AB u njenoj najranijoj fazi. Nadamo se da će različiti aspekti istraživanja Alzheimerove bolesti pridonijeti razvoju novih oblika liječenja i/ili prevencije ove još uvijek neizlječive bolesti .Alzheimer’s disease (AD) is the most common form of dementi a. Although the disease and its main pathological features, senile plaques and neurofi brillary tangles, have been discovered over 100 years ago, there is sti ll no adequate therapy that would treat, slow progression or prevent the genesis of Alzheimer’s disease. Since altered metabolism of the β-amyloid precursor protein (APP) and altered formati on of amyloid-β pepti de (Aβ) play a central role in the pathogenesis of Alzheimer’s disease, understanding their mechanism of formati on and clearance is important for designing new therapies for AD. Development of novel diagnosti c methods that will enable early and accurate diagnosis of AD is of high importance. It is esti mated that any new interventi on against AD will have its greatest eff ect if applied early in the pathogenesis of the disease, when the brain is not that much aff ected. Anaylsis of the three proteins in the cerebrospinal fl uid (CSF) (Aβ42, total tau and phoshotau) gave the best results unti l now and showed that this test could be used for diff erenti al diagnosis of AD as well as for diagnosis of non-demented individuals and mildly cogniti vely impaired (MCI) individuals who will progress to AD in the future. Thus, the goal of the biomarker research is to identi fy changes that will diagnose AD in its earliest stage. We hope that diff erent aspects of reserach on AD will generate novel therapies and/or will help in preventi ng Alzheimer’s disease

Niemann Pick type C cells show cholesterol dependent decrease of APP expression at the cell surface and its increased processing through the β-secretase pathway

The link between cholesterol and Alzheimer’s disease has recently been revealed in Niemann Pick type C disease. We found that NPC1-/- cells show decreased expression of APP at the cell surface and increased processing of APP through the β-secretase pathway resulting in increased C99, sAPPβ and intracellular Aβ40 levels. This effect is dependent on increased cholesterol levels, since cholesterol depletion reversed cell surface APP expression and lowered Aβ/C99 levels in NPC1-/- cells to the levels observed in wt cells. Finding that overexpression of C99, a direct gamma-secretase substrate, does not lead to increased intracellular Aβ levels in NPC1-/- cells vs. CHOwt suggests that the effect on intracellular Aβ upon cholesterol accumulation in NPC1-/- cells is not due to increased APP cleavage by gamma-secretase. Our results indicate that cholesterol may modulate APP processing indirectly by modulating APP expression at the cell surface and, thus, its cleavage by β-secretase

Cholesterol-depletion corrects APP and BACE1 misstrafficking in NPC1-deficient cells

Cholesterol accumulation in Niemann-Pick type C disease (NPC) causes increased levels of the amyloid-precursor-protein C-terminal fragments (APP-CTFs) and intracellular amyloid-β peptide (Aβ), the two central molecules in Alzheimer’s disease (AD) pathogenesis. We previously reported that cholesterol accumulation in NPC-cells leads to cholesterol-dependent increased APP processing by β-secretase (BACE1) and decreased APP expression at the cell surface (Malnar et al. Biochim Biophys Acta. 1802 (2010) 682-691.). We hypothesized that increased formation of APP-CTFs and Aβ in NPC disease is due to cholesterol-mediated altered endocytic trafficking of APP and/or BACE1. Here, we show that APP endocytosis is prerequisite for enhanced Aβ levels in NPC-cells. Moreover, we observed that NPC cells show cholesterol dependent sequestration and colocalization of APP and BACE1 within enlarged early/recycling endosomes which can lead to increased β-secretase processing of APP. We demonstrated that increased endocytic localization of APP in NPC-cells is likely due to both its increased internalization and its decreased recycling to the cell surface. Our findings suggest that increased cholesterol levels, such as in NPC disease and sporadic AD, may be the upstream effector that drives amyloidogenic APP processing characteristic for Alzheimer's disease by altering endocytic trafficking of APP and BACE1