Changes in the makeup of gut microbiota are linked to many neuropsychiatric diseases. Although the exact connection between gut dysbiosis and brain dysfunction is not yet fully understood, but recent data suggests that gut dysbiosis may contribute to the development of Alzheimer's disease (AD) by promoting neuroinflammation, insulin resistance, oxidative stress, and amyloid-beta (Aβ) aggregation. Gut dysbiosis in animal models is primarily characterized by an elevated ratio of Firmicutes/Bacteroidetes which may lead to the accumulation of amyloid precursor protein (APP) in the intestine, in the early stages of AD. Probiotics play a significant role in preventing against the symptoms of AD by restoring gut-brain homeostasis. This chapter provides an overview of the gut microbiota and its dysregulation in etiology of AD. Moreover, novel insights into alteration of the composition of gut microbiota as a preventive or therapeutic approach to AD are discussed.

• MeSH
• Alzheimerova nemoc * mikrobiologie   metabolismus   patofyziologie   MeSH
• dysbióza * komplikace   metabolismus   MeSH
• lidé MeSH
• probiotika terapeutické užití   MeSH
• střevní mikroflóra * fyziologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Accumulation of misfolded α-synuclein (α-Syn) leads to the formation of Lewy bodies and is a major hallmark of Parkinson's disease (PD). The accumulation of α-Syn involves several post-translational modifications. Recently, though, glycation of α-Syn (advanced glycation end products) and activation of the receptor for advanced glycation end products (RAGE) have been linked to neuroinflammation, which leads to oxidative stress and accumulation of α-Syn. The present study aims to detect the effect of glycated α-Syn (gly-α-Syn)-induced synucleinopathy and loss of dopaminergic (DAergic) neurons in the development of PD. We isolated, purified, and prepared glycated recombinant human α-Syn using d-ribose. Gly-α-Syn was characterized by SDS-PAGE, intact mass analysis, and bottom-up peptide sequence through LC-HRMS/MS. The aggregation propensity of gly-α-Syn has been verified by morphological and shape analysis through Bio-AFM. The gly-α-Syn (2 μg/μL) was injected stereotaxically in the substantia nigra (SN) of ICR mice (3-4 months) and compared with the normal α-Syn, d ribose, and Tris-HCl/artificial CSF groups. 56 days postsurgery (DPS), an immunohistochemical examination was conducted to investigate gly-α-Syn-induced α-Syn accumulation, neuroinflammation, and neurodegeneration. The glycation of α-Syn led to the expression of transglutaminase 2 (TGM2), an enzyme that cross-linked with AGEs and may have caused the accumulation of α-Syn. Significant RAGE activation was also observed in gly-α-Syn, which might have induced glial cell activation, resulting in oxidative stress and, ultimately, apoptosis of dopaminergic neurons. It is important to note that TGM2, phosphorylated α-Syn, RAGE expression, and glial cell activation were only found in the gly-α-Syn group and not in the other groups. This suggests that gly-α-Syn plays a major role in synucleinopathy, neuroinflammation, and neurodegeneration. Overall, the present study demonstrated glycation of α-Syn as one of the important age-associated post-translational modifications that are involved in the degeneration of dopaminergic neurons, at least in a subset of the diabetic patients susceptible to developing PD.

• MeSH
• alfa-synuklein * metabolismus   MeSH
• dopaminergní neurony * metabolismus   patologie   účinky léků   MeSH
• glykosylace MeSH
• lidé MeSH
• myši inbrední ICR MeSH
• myši MeSH
• neuroglie * metabolismus   patologie   účinky léků   MeSH
• oxidační stres MeSH
• Parkinsonova nemoc * metabolismus   patologie   MeSH
• produkty pokročilé glykace metabolismus   MeSH
• receptor pro konečné produkty pokročilé glykace metabolismus   MeSH
• substantia nigra metabolismus   patologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Apolipoprotein E (APOE) is distributed across various human tissues and plays a crucial role in lipid metabolism. Recent investigations have uncovered an additional facet of APOE's functionality, revealing its role in host defense against bacterial infections. To assess the antibacterial attributes of APOE3 and APOE4, we conducted antibacterial assays using Pseudomonas aeruginosa and Escherichia coli. Exploring the interaction between APOE isoforms and lipopolysaccharides (LPSs) from E. coli, we conducted several experiments, including gel shift assays, CD, and fluorescence spectroscopy. Furthermore, the interaction between APOE isoforms and LPS was further substantiated through atomic resolution molecular dynamics simulations. The presence of LPS induced the aggregation of APOE isoforms, a phenomenon confirmed through specific amyloid staining, as well as fluorescence and electron microscopy. The scavenging effects of APOE3/4 isoforms were studied through both in vitro and in vivo experiments. In summary, our study established that APOE isoforms exhibit binding to LPS, with a more pronounced affinity and complex formation observed for APOE4 compared with APOE3. Furthermore, our data suggest that APOE isoforms neutralize LPS through aggregation, leading to a reduction of local inflammation in experimental animal models. In addition, both isoforms demonstrated inhibitory effects on the growth of P. aeruginosa and E. coli. These findings provide new insights into the multifunctionality of APOE in the human body, particularly its role in innate immunity during bacterial infections.

• MeSH
• apolipoprotein E3 * metabolismus   chemie   farmakologie   MeSH
• apolipoprotein E4 * metabolismus   chemie   farmakologie   MeSH
• Escherichia coli metabolismus   MeSH
• lidé MeSH
• lipopolysacharidy * metabolismus   chemie   MeSH
• myši MeSH
• protein - isoformy chemie   metabolismus   MeSH
• Pseudomonas aeruginosa metabolismus   MeSH
• simulace molekulární dynamiky MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

The amyloid cascade hypothesis postulates that extracellular deposits of amyloid β (Aβ) are the primary and initial cause leading to the full development of Alzheimer's disease (AD) with intracellular neurofibrillary tangles; however, the details of this mechanism have not been fully described until now. Our preliminary data, coming from our day-to-day neuropathology practice, show that the primary location of the hyperphosphorylated tau protein is in the vicinity of the cell membrane of dystrophic neurites. This observation inspired us to formulate a hypothesis that presumes an interaction between low-density lipoprotein receptor-related protein 1 (LRP1) and fibrillar aggregates of, particularly, Aβ42 anchored at the periphery of neuritic plaques, making internalization of the LRP1-Aβ42 complex infeasible and, thus, causing membrane dysfunction, leading to the tauopathy characterized by intracellular accumulation and hyperphosphorylation of the tau protein. Understanding AD as a membrane dysfunction tauopathy may draw attention to new treatment approaches not only targeting Aβ42 production but also, perhaps paradoxically, preventing the formation of LRP1-Aβ42.

• MeSH
• Alzheimerova nemoc * metabolismus   patologie   etiologie   MeSH
• amyloidní beta-protein * metabolismus   MeSH
• buněčná membrána metabolismus   MeSH
• fosforylace MeSH
• lidé MeSH
• peptidové fragmenty metabolismus   MeSH
• protein 1 související s LDL-receptory * metabolismus   MeSH
• proteiny tau * metabolismus   MeSH
• tauopatie * metabolismus   patologie   etiologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Waldenströmova makroglobulinémie (WM) patří k low-grade B-lymfomům. Je definována přítomností lymfoplazmocytárního lymfomu v kostní dřeni a monoklonálního imunoglobulinu typu IgM (M-IgM) v séru. Příznaky nemoci, anémie a trombocytopenie, mohou souviset s masou patologických buněk, stejně jako systémové zánětlivé projevy (B-symptomy). Velké spektrum symptomů však způsobuje M-IgM. Koncentrace M-IgM u WM nekoreluje s masou patologických buněk. Spektrum poruch způsobených M-IgM je vzhledem k diverzitě patofyziologických mechanizmů a lokalizaci poškození značně široké. Poškození může vzniknout depozicí kompletní molekuly nebo její části ve formě agregátů, amorfních, krystalických, mikrotubulárních či fibrilárních struktur. M-IgM může také pacienta poškozovat autoprotilátkovou aktivitou namířenou proti antigenům vlastních tkání. Dále může M-IgM tvořit imunitní komplexy a aktivovat komplement. Výjimečně může B buněčný klon indukovat tvorbu cytokinů. Proto je velmi obtížené včas rozpoznat symptomatickou formu WM. V této publikaci popisujeme pacientku poškozenou depozity M-IgM a řetězců lambda. Diskuze je zaměřena na přehled všech forem poškození člověka depozity M-IgM, mezi něž patří i popsaný případ.

Waldenström’s macroglobulinaemia (WM) is a low-grade B-cell lymphoproliferative disorder characterised by an immunoglobulin IgM monoclonal gammopathy and bone marrow infiltration by lymphoplasmacytic lymphoma. Clinical features may be related to the overall disease burden, such as anaemia, thrombocytopenia, and constitutional inflammatory symptoms, or may be directly attributable to the IgM paraprotein. The concentration of monoclonal IgM can vary widely in WM. There is no direct relationship between the concentration of monoclonal immunoglobulin IgM and bone marrow infiltration. The spectrum of monoclonal immunoglobulin IgM-related disorders is large because of the diversity of involved organs and pathogenic mechanisms. Lesions commonly result from the deposition of all or part of the M-IgM as aggregates, amorphous, crystalline, microtubular, or fibrillar forms. Other mechanisms include autoantibody activity against a tissue antigen, formation of immune complexes, and complement activation. In addition, even a small B-cell clone may absorb biologically active molecules or induce cytokine secretion. In our case report, we describe a female patient with monoclonal IgM and lambda liver deposition and we discuss the frequency and variety of disorders caused by deposition of monoclonal IgM and free light chain.

• Klíčová slova
• imunokomplexy,
• MeSH
• amyloid imunologie   klasifikace   MeSH
• amyloidóza diagnóza   imunologie   klasifikace   patologie   MeSH
• hepatomegalie etiologie   imunologie   MeSH
• imunoglobulin M imunologie   krev   škodlivé účinky   MeSH
• krevní nemoci diagnóza   etiologie   krev   MeSH
• lidé středního věku MeSH
• lidé MeSH
• Waldenströmova makroglobulinemie * diagnostické zobrazování   diagnóza   imunologie   patologie   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• kazuistiky MeSH
• práce podpořená grantem MeSH

INTRODUCTION: ALZ-801/valiltramiprosate is a small-molecule oral inhibitor of beta amyloid (Aβ) aggregation and oligomer formation being studied in a phase 2 trial in APOE4 carriers with early Alzheimer's disease (AD) to evaluate treatment effects on fluid and imaging biomarkers and cognitive assessments. METHODS: The single-arm, open-label phase 2 trial was designed to evaluate the effects of the ALZ-801 265 mg tablet taken twice daily (after 2 weeks once daily) on plasma fluid AD biomarkers, hippocampal volume (HV), and cognition over 104 weeks in APOE4 carriers. The study enrolled subjects aged 50-80 years, with early AD [Mini-Mental State Examination (MMSE) ≥ 22, Clinical Dementia Rating-Global (CDR-G) 0.5 or 1], apolipoprotein E4 (APOE4) genotypes including APOE4/4 and APOE3/4 genotypes, and positive cerebrospinal fluid (CSF) AD biomarkers or prior amyloid scans. The primary outcome was plasma p-tau181, HV evaluated by magnetic resonance imaging (MRI) was the key secondary outcome, and plasma Aβ42 and Aβ40 were the secondary biomarker outcomes. The cognitive outcomes were the Rey Auditory Verbal Learning Test and the Digit Symbol Substitution Test. Safety and tolerability evaluations included treatment-emergent adverse events and amyloid-related imaging abnormalities (ARIA). The study was designed and powered to detect 15% reduction from baseline in plasma p-tau181 at the 104-week endpoint. A sample size of 80 subjects provided adequate power to detect this difference at a significance level of 0.05 using a two-sided paired t-test. RESULTS: The enrolled population of 84 subjects (31 homozygotes and 53 heterozygotes) was 52% females, mean age 69 years, MMSE 25.7 [70% mild cognitive impairment (MCI), 30% mild AD] with 55% on cholinesterase inhibitors. Plasma p-tau181 reduction from baseline was significant (31%, p = 0.045) at 104 weeks and all prior visits; HV atrophy was significantly reduced (p = 0.0014) compared with matched external controls from an observational Early AD study. Memory scores showed minimal decline from baseline over 104 weeks and correlated significantly with decreased HV atrophy (Spearman's 0.44, p = 0.002). Common adverse events were COVID infection and mild nausea, and no drug-related serious adverse events were reported. Of 14 early terminations, 6 were due to nonserious treatment-emergent adverse events and 1 death due to COVID. There was no vasogenic brain edema observed on MRI over 104 weeks. CONCLUSIONS: The effect of ALZ-801 on reducing plasma p-tau181 over 2 years demonstrates target engagement and supports its anti-Aβ oligomer action that leads to a robust decrease in amyloid-induced brain neurodegeneration. The significant correlation between reduced HV atrophy and cognitive stability over 2 years suggests a disease-modifying effect of ALZ-801 treatment in patients with early AD. Together with the favorable safety profile with no events of vasogenic brain edema, these results support further evaluation of ALZ-801 in a broader population of APOE4 carriers, who represent two-thirds of patients with AD. TRIAL REGISTRATION: https://clinicaltrials.gov/study/NCT04693520 .

• MeSH
• Alzheimerova nemoc * farmakoterapie   diagnostické zobrazování   MeSH
• amyloidní beta-protein * MeSH
• aplikace orální MeSH
• apolipoprotein E4 * genetika   MeSH
• biologické markery * krev   MeSH
• heterozygot MeSH
• hipokampus * účinky léků   diagnostické zobrazování   MeSH
• kognice * účinky léků   MeSH
• lidé středního věku MeSH
• lidé MeSH
• magnetická rezonanční tomografie MeSH
• peptidové fragmenty krev   MeSH
• proteiny tau MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze II MeSH

Jsou shrnuty poznatky o rizikových faktorech a biomarkerech Alzheimerovy nemoci (AD), které jsou základem pro poznání patofyziologie onemocnění a pro rozpoznání buněčných cílů nových léčiv. Hlavními cíli nových léčiv pro AD jsou procesy spojené s neurotoxicitou amyloidu beta (A?) a tau proteinu, narušenou neurotransmisí, metabolickou dysregulací, mitochondriální dysfunkcí, oxidačním stresem, neurozánětem, neuroplasticitou, proteostází a proteinopatií. Některá nová léčiva jsou zaměřena na více asociovaných buněčných procesů, jako je cholinergní deplece, toxicita glutamátu, agregace A?, hyperfosforylace tau, oxidační stres a aktivita mitochondriálních proteinů. Farmakologická intervence při AD s potenciálem být kauzální zahrnuje regulaci produkce, eliminace, šíření a vzájemné interakce oligomerů a agregátů A? (k prevenci nástupu onemocnění), oligomerů tau a neurofibrilárních klubek (k eliminaci progrese onemocnění) a mitochondriální dysfunkce (ke snížení progrese neurodegenerace). Účinnost farmakoterapie lze zvýšit vhodnou kombinací s jinými lékovými i nelékovými intervencemi a doplňky stravy.

Knowledge about risk factors and biomarkers of Alzheimer ́s disease (AD), which are the basis for understanding the pathophysiology of the disease and for identifying the cellular targets for new drugs, is summarized. The main targets of new AD drugs are processes associated with amyloid beta (A?) and tau neurotoxicity, impaired neurotransmission metabolic dysregulation, mitochondrial dysfunction, oxidative stress, neuroinflammation, neuroplasticity, proteostasis, and proteinopathy. Some new drugs target multiple associated cellular processes, such as cholinergic depletion, glutamate toxicity, A? aggregation, tau hyperphosphorylation, oxidative stress, and mitochondrial protein activity. Pharmacological intervention in AD with the potential to be causal includes targeting the production, elimination, distribution, and interactions of A? oligomers and aggregates (to prevent disease onset), tau oligomers and neurofibrillary tangles (to prevent disease progression), and mitochondrial dysfunction (to reduce neurodegeneration progression). The effectiveness of pharmacotherapy may be enhanced by appropriate combination with other drug and non-drug interventions and nutritional supplements.

Several scientific evidences report that a central role in the pathogenesis of Alzheimer's disease is played by the deposition of insoluble aggregates of β-amyloid proteins in the brain. Because Aβ is self-assembling, one possible design strategy is to inhibit the aggregation of Aβ peptides using short peptide fragments homologous to the full-length wild-type Aβ protein. In the past years, several studies have reported on the synthesis of some short synthetic peptides called β-sheet breaker peptides (BSBPs). Herein, we present the synthesis of novel (cell-permeable) N-methyl BSBPs, designed based on literature information on the structural key features of BSBPs. Three-dimensional GRID-based pharmacophore peptide screening combined with PT-WTE metadynamics was performed to support the results of the design and microwave-assisted synthesis of peptides 2 and 3 prepared and analyzed for their fibrillogenesis inhibition activity and cytotoxicity. An HR-MS-based cell metabolomic approach highlighted their cell permeability properties.

• Publikační typ
• časopisecké články MeSH

Alzheimer's disease (AD) is a very common neurodegenerative disorder associated with memory loss and a progressive decline in cognitive activity. The two major pathophysiological factors responsible for AD are amyloid plaques (comprising amyloid-beta aggregates) and neurofibrillary tangles (consisting of hyperphosphorylated tau protein). Polyphenols, a class of naturally occurring compounds, are immensely beneficial for the treatment or management of various disorders and illnesses. Naturally occurring sources of polyphenols include plants and plant-based foods, such as fruits, herbs, tea, vegetables, coffee, red wine, and dark chocolate. Polyphenols have unique properties, such as being the major source of anti-oxidants and possessing anti-aging and anti-cancerous properties. Currently, dietary polyphenols have become a potential therapeutic approach for the management of AD, depending on various research findings. Dietary polyphenols can be an effective strategy to tackle multifactorial events that occur with AD. For instance, naturally occurring polyphenols have been reported to exhibit neuroprotection by modulating the Aβ biogenesis pathway in AD. Many nanoformulations have been established to enhance the bioavailability of polyphenols, with nanonization being the most promising. This review comprehensively provides mechanistic insights into the neuroprotective potential of dietary polyphenols in treating AD. It also reviews the usability of dietary polyphenol as nanoformulation for AD treatment.

• MeSH
• Alzheimerova nemoc * farmakoterapie   dietoterapie   metabolismus   MeSH
• amyloidní beta-protein metabolismus   MeSH
• biologická dostupnost MeSH
• dieta MeSH
• lidé MeSH
• nanočástice chemie   MeSH
• neuroprotektivní látky terapeutické užití   farmakologie   MeSH
• polyfenoly * farmakologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Demencia s Lewyho telieskami (DLB) predstavuje 10–15 % všetkých prípadov demencie. Neuropatologicky je DLB charakterizovaná akumuláciou agregovaného proteínu α-synukleínu v Lewyho telieskach a Lewyho neuritoch, podobne ako je to pri Parkinsonovej chorobe (PD). Extrapyramídové motorické symptómy charakteristické pre PD sú u pacientov s DLB bežné, avšak nie sú pre klinickú diagnózu DLB nevyhnutné. Prekryv s patológiou typickou pre Alzheimerovu chorobu (AD) je taktiež často pozorovaným javom, ako na úrovni klinického obrazu, tak na úrovni neuropatologických zmien. Konsenzuálne kritéria pre diagnostiku DLB sa opierajú o typickú klinickú symptomatológiu a tiež o prítomnosť charakteristických biomarkerov. Prítomnosť oslabenej dopaminergnej neurotransmisie v bazálnych gangliách či charakteristických polysomnografických nálezov poukazujúcich na poruchu správania v REM spánku napo- máha správnej diagnostike tohto závažného neurodegeneratívneho ochorenia. V súčasnosti žiaľ neexistuje žiadna kauzálna liečba DLB. Inhibítory acetylcholínesterázy (AChE), schválené pre Alzheimerovu chorobu, sú používané taktiež pri terapii DLB. Veľká opatrnosť je nutná pri podávaní antidopaminergných látok, na ktoré sú pacienti s DLB výrazne citliví, s rizikom závažných nežiadúcich účinkov.

Dementia with Lewy bodies (DLB) accounts for 10–15 % of all dementia cases. Neuropathologically, DLB is characterized by the accumulation of aggregated protein α-synuclein in Lewy bodies and Lewy neurites, similar to Parkinson’s disease (PD). Extrapyramidal motor symptoms of PD are common in patients with DLB, but are not essential for a clinical diagnosis of DLB. Overlap with the pathology typical of Alzheimer’s disease (AD) is also frequently observed both at the level of the clinical picture as well as neuropathological changes. Consensus criteria for the diagnosis of DLB are based on typical clinical symptomatology and also on the presence of characteristic biomarkers. The presence of reduced dopaminergic neurotransmission in the basal ganglia or characteristic polysomnographic findings indicating a behavior disorder in REM sleep helps in the correct diagnosis of this serious neurodegenerative disease. Unfortunately, there is currently no causal treatment for DLB. Acetylcholinesterase (AChE) inhibitors, approved for Alzheimer’s disease, are also used in DLB therapy. Caution is required when administering antidopaminergic agents, because of the risk of serious adverse effects.

• MeSH
• alfa-synuklein škodlivé účinky   toxicita   MeSH
• antagonisté dopaminu škodlivé účinky   MeSH
• antipsychotika škodlivé účinky   terapeutické užití   MeSH
• biologické markery analýza   MeSH
• cholinesterasové inhibitory terapeutické užití   MeSH
• demence s Lewyho tělísky * diagnóza   farmakoterapie   genetika   MeSH
• diferenciální diagnóza MeSH
• Lewyho tělíska patologie   MeSH
• lidé MeSH
• patologické stavy, příznaky a symptomy MeSH
• věk při počátku nemoci MeSH
• Check Tag
• lidé MeSH