Background: Depression is associated with Alzheimer’s disease (AD). Objective: To evaluate the association between depressive symptoms and age of onset of cognitive decline in autosomal dominant AD, and to determine possible factors associated to early depressive symptoms in this population. Methods: We conducted a retrospective study to identify depressive symptoms among 190 presenilin 1 (PSEN1) E280A mutation carriers, subjected to comprehensive clinical evaluations in up to a 20-year longitudinal follow-up. We controlled for the following potential confounders: APOE, sex, hypothyroidism, education, marital status, residence, tobacco, alcohol, and drug abuse. Results: PSEN1 E280A carriers with depressive symptoms before mild cognitive impairment (MCI) develop dementia faster than E280A carriers without depressive symptoms (Hazard Ratio, HR = 1.95; 95% CI, 1.15–3.31). Not having a stable partner accelerated the onset of MCI (HR = 1.60; 95 % CI, 1.03–2.47) and dementia (HR = 1.68; 95 % CI, 1.09–2.60). E280A carriers with controlled hypothyroidism had later age of onset of depressive symptoms (HR = 0.48; 95 % CI, 0.25–0.92), dementia (HR = 0.43; 95 % CI, 0.21–0.84), and death (HR = 0.35; 95 % CI, 0.13–0.95). APOE ɛ2 significantly affected AD progression in all stages. APOE polymorphisms were not associate to depressive symptoms. Women had a higher frequency and developed earlier depressive symptoms than men throughout the illness (HR = 1.63; 95 % CI, 1.14–2.32). Conclusion: Depressive symptoms accelerated progress and faster cognitive decline of autosomal dominant AD. Not having a stable partner and factors associated with early depressive symptoms (e.g., in females and individuals with untreated hypothyroidism), could impact prognosis, burden, and costs.
Dysfunction in the neurovascular unit (NVU) is a key component in the progressive deterioration of Alzheimer’s disease (AD) and is critical in vascular dementia. Recent studies have shown that inflammation plays early and perhaps causal roles in the pathogenesis of AD related to NVU damage, possibly in part by overactivating the aspartic acid protease activity of β-site amyloid precursor protein-cleaving enzyme 1 (BACE1), which until now has almost solely been studied in the context of the β-amyloid cascade. In this study, we analyzed the relationship of BACE1 with astrocytes and blood vessels in human brains with sporadic and familial dementia [Autosomal dominant cerebral arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), sporadic Alzheimer’s disease (SAD), and familial Alzheimer’s disease (FAD)] and how BACE1 inhibition affects astrocytes and endothelial cells under conditions of glutamate toxicity. Our results show increased BACE1, PHF (Paired helical filaments)-tau and GFAP (Glial Fibrillary Acid Protein) immunoreactivity (IR) in the CA1 hippocampal regions of FAD and SAD brains. Furthermore, BACE1 immunoprecipitated with GFAP in tissue samples from all study cases, but their immunofluorescence close to (10 μm3) or overlapping blood vessels was only increased in FAD and SAD brains, and PHF-tau was present around the vessels mainly in FAD brains. Interestingly, the increased BACE1 levels were associated with reactive astrocytes, characterized by morphological changes and upregulation of GFAP under pathological and stressful conditions, and endothelial disruption by glutamate excitotoxicity, and these effects were reversed by BACE1 inhibition; further, BACE1-inhibited astrocytes protected endothelial cell integrity by preserving zonula occludens-1 (ZO-1) distribution and decreasing the expression of inflammatory markers. Taken together, these findings suggest that BACE1 dysregulation in astrocytes may have a role in the alterations in NVU integrity implicated in neurodegeneration.
C-terminal binding proteins (CtBP1/2) are transcriptional coregulators that play a significant role during vertebrate neurodevelopment. This systematic review aims to identify case reports with genetic variants in CTBP1 and CTBP2 associated with brain development syndromes.We screened different databases (PubMed, Scopus, Google Scholar, LILACS) by systematically searching journals and checking reference lists and citations of background papers. We found fourteen cases (10 males) from five papers carrying two pathogenic, heterozygous variants in the CTBP1 gene (13 individuals carried the missense mutation c.991C T, p.Arg342Trp, and one subject carrying the 2-base pair deletion c.1315_1316delCA, p.Gln439ValfsTer84). These mutations were de novo in 13 cases and one case of maternal germinal mosaicism. Two variants are in the same domain of the protein: Pro-Leu-Asp-Leu-Ser (PLDLS) C terminal. Patients with these mutations exhibit a phenotype with intellectual disability, HADDTS syndrome (hypotonia, ataxia, developmental delay, and tooth enamel defects), and cerebellar volume loss. We did not identify reported cases associated with homozygous mutations harbored in CTBP1. We did not identify any report of neurodevelopment phenotypes associated with heterozygous or homozygous CTBP2 mutations. Due to CTBP2/RIBEYE being a gene with dual function, identifying and interpreting the potential pathogenic variants is challenging.Further, homozygous mutations in the CTBP2 gene may be lethal. The mechanisms involved in the pathogenesis of neurodevelopment due to variants of these proteins have not yet been elucidated, despite some functional evidence. Further studies should be conducted to understand these transcription factors and their interaction with each other and their partners.
In the late phase of Trypanosoma cruzi infection, parasite persistence and an exaggerated immune response accompanied by oxidative stress play a crucial role in the genesis of Chronic Chagasic Cardiomyopathy (CCC). Current treatments (Benznidazole (BNZ) and Nifurtimox) can effect only the elimination of the parasite, but are ineffective for late stage treatment and for preventing heart damage and disease progression. In vivo trypanocidal and cardioprotective activity has been reported for Lippia alba essential oils (EOs), ascribed to their two major terpenes, limonene and caryophyllene oxide. To investigate the role of antioxidant and immunomodulatory mechanisms behind these properties, chronic-T. cruzi-infected rats were treated with oral synergistic mixtures of the aforementioned EOs. For this purpose, the EOs were optimized through limonene-enrichment fractioning and by the addition of exogenous caryophyllene oxide (LIMOX) and used alone or in combined therapy with subtherapeutic doses of BNZ (LIMOXBNZ). Clinical, toxicity, inflammatory, oxidative, and parasitological (qPCR) parameters were assessed in cardiac tissue. These therapies demonstrated meaningful antioxidant and immunomodulatory activity on markers involved in CCC pathogenesis (IFN-γ, TNF-α, IL-4, IL-10, and iNOS), which could explain their significant trypanocidal properties and their noteworthy role in preventing, and even reversing, the progression of cardiac damage in chronic Chagas disease.
Background β‐amyloid (βA) is a highly conserved peptide throughout the evolution of species that has been proposed as a participant in vital functions. This peptide has been related to the onset and progression of Alzheimer’s disease (AD). Additionally, recent scientific reports have demonstrated in vitro activity against bacteria, fungi and virus. The aim of this study is to describe the colocalization between βA and bacteria in postmortem brain tissue of patients with familial AD. Method Initially, we observed bacterial accumulations in brain tissue of two patients with familial Alzheimer's disease and in one case colocalization of βA with bacteria was observed. In order to confirm whether this finding was repeated, shortly after donation and before being fixed with formaldehyde, five cases fresh cerebral samples from five cases with early onset AD were immediately inoculated in vitro with Enterococcus faecalis and Lactobacillus rhamnosus. After different periods of time, both immunostaining for βA detection and Gram staining for bacteria observation were performed on each sample. Result Colocalization of βA and gram positive bacteria were observed in all cases. In those infected in vitro, the phenomenon was observed after a period of 24 h of incubation at 35 °C. In the cases fixed with formaldehyde to 10%, its observed multiples cavitations macroscopic in white substance throughout the brain Conclusion These results suggest that the βA agglutinates the bacteria, then it’s possible a relationship between βA and bacteria, possibly due to the antimicrobial activity that has been attributed to βA. However, it is necessary to carry out studies with a larger number of samples to confirm the phenomenon and to attempt to explicate it from the cellular and molecular points of view.
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