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

Oxidative stress parameters in plasma of Huntington's disease patients, asymptomatic Huntington's disease gene carriers and healthy subjects : a cross-sectional study

BACKGROUND : Animal data and postmortem studies suggest a role of oxidative stress in the Huntington's disease (HD), but in vivo human studies have been scarce. ----- AIM : To assess the presence of oxidative stress in HD patients and its occurrence relative to clinical symptoms. ----- METHODS : Oxidative stress markers were determined in plasma of HD patients (n = 19), asymptomatic HD gene carriers (with > 38 CAG repeats) (n = 11) and their respective sex and agematched healthy controls (n = 47 and n = 22) in a cross-sectional study. ----- RESULTS : With adjustment for age and sex, HD patients had higher plasma lipid peroxidation (LP) levels (ratio 1.20, 95% CI 1.09 to 1.32, p < 0.001) and lower reduced glutathione (GSH) levels (ratio 0.72, CI 0.55 to 0.94, p = 0.011) than their age and sex-matched controls. Although considerably younger, HD gene carriers did not differ from HD patients regarding LP and GSH levels, and had higher plasma LP (ratio 1.16, CI 1.02 to 1.32, p = 0.016) and lower GSH than their matched controls (ratio 0.73, CI 0.5 to 1.05). They had higher LP (ratio 1.18, CI 1.02 to 1.34, p = 0.019) and lower GSH (ratio 0.75, CI 0.51 to 1.11) than the healthy subjects matched to HD patients. ----- CONCLUSIONS : Oxidative stress is more pronounced in HD patients and asymptomatic HD gene carriers than in healthy subjects. Differences in plasma LP and GSH are in line with the brain findings in animal models of HD. Data suggest that oxidative stress occurs before the onset of the HD symptoms

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

Lumbalna spondiloptoza nakon teške politraume: prikaz slučaja

A rare case of thoracolumbar spondyloptosis after a severe polytraumatic event is presented. Spondyloptosis accounts for a minor proportion of all spine trauma cases and is usually accompanied by complete neurological deficit. A 48-year-old man suffered severe polytrauma after having been hit by a truck at the work place. Radiographic scanning revealed multiple traumatic injuries and spondyloptosis at the L1/L2 level in coronal plane. However, despite extensive injuries, ASIA score was estimated as D. The patient underwent urgent multidisciplinary surgery due to severe head injuries. The next surgery was performed to stabilize the thoracolumbar segment and to preserve neurological functions. The surgery included implantation of transpedicular titanium screws via posterior approach. Good postoperative recovery was achieved during early postoperative rehabilitation at our Department, which was estimated as ASIA score D. In conclusion, prompt operative treatment to achieve neural integrity and early rehabilitation should be considered as the gold standard in such complicated injuries. Postoperative recovery largely depends on the quality of rehabilitation, which leads to improvement of patient self-care and normal social and psychological functions. In our case, the good preoperative neurological status of the patient also contributed to better postoperative outcome.Prikazuje se rijedak slučaj torako-lumbalne spondiloptoze nakon teške politraume. Manji udio svih trauma kralježnice odnosi se na spondiloptoze koje su najčešće popraćene potpunim neurološkim deficitom. Muškarac u dobi od 48 godina na radnom mjestu zadobio je politraumatske ozljede nakon udarca kamiona. Radiološka obrada pokazala je višestruke traumatske ozljede i spondiloptozu segmenta L 1/L 2 u koronarnoj projekciji. Unatoč ovoj opsežnoj traumi kralježnice ozljeda je prema ljestvici ASIA procijenjena kao D. Bolesniku je učinjen hitni multidisciplinski operacijski zahvat u svrhu zbrinjavanja teških ozljeda glave. Sljedećoj operaciji pristupljeno je radi stabilizacije torako-lumbalnog segmenta i s ciljem očuvanja neuroloških funkcija. Operacija je učinjena uobičajenim stražnjim pristupom te implantacijom transpedikularnih vijaka. Zadovoljavajući poslijeoperacijski oporavak postignut je tijekom rane poslijeoperacijske rehabilitacije u Klinici, procijenjen kao ASIA D. Izvrstan poslijeoperacijski oporavak potvrđen je daljnjom ambulantnom kontrolom bolesnika, uz učinjene neurološke testove. Poslijeoperacijska neurorehabilitacija smatra se nužnom za što bolji oporavak fizioloških funkcija u ovakvim životno ugrožavajućim nesrećama

Novel amino-β-lactam derivatives as potent cholesterol absorption inhibitors

Two new trans-(3R, 4R)-amino-β-lactam derivatives and their diastereoisomeric mixtures were synthesized as ezetimibe bioisosteres and tested in in vitro and in vivo experiments as novel β-lactam cholesterol absorption inhibitors. Both compounds exhibited low cytotoxicity in MDCKII, hNPC1L1/MDCKII, and HepG2 cell lines and potent inhibitory effect in hNPC1L1/MDCKII cells. In addition, these compounds markedly reduced cholesterol absorption in mice, resulting in reduced cholesterol concentrations in plasma, liver, and intestine. We determined the crystal structure of one amino-β-lactam derivative to establish unambiguously both the absolute and relative configuration at the new stereogenic centre C17, which was assigned to be S. The pKa values for both compounds are 9.35, implying that the amino-β-lactam derivatives and their diastereoisomeric mixtures are in form of ammonium salt in blood and the intestine. The IC50 value for the diastereoisomeric mixture is 60 μM. In vivo, it efficiently inhibited cholesterol absorption comparable to ezetimibe