The accumulation of abnormal phosphorylated Tau protein (pTau) in neurons of the brain is a pathological hallmark of Alzheimer’s disease (AD). PTau pathology also occurs in the retina of AD cases. Accordingly, questions arise whether retinal pTau can act as a potential seed for inducing cerebral pTau pathology and whether retinal pTau pathology causes degeneration of retinal neurons. To address these questions, we (1) characterized pTau pathology in the retina of TAU58 mice, (2) determined the impact of pTau pathology on retinal ganglion cell density, and (3) used this mouse model to test whether brain lysates from AD and/or non-AD control cases induce seeding in the retina and/or propagation into the brain. TAU58 mice developed retinal pTau pathology at 6 months of age, increasing in severity and extent with age. TAU58 mice showed reduced retinal ganglion cell density compared to wild-type mice, which declined with age and pTau pathology progression. Brain lysates from non-AD Braak neurofibrillary tangle (NFT) stage I controls increased retinal pTau pathology after subretinal injection compared to phosphate-buffered saline (PBS) but did not accelerate pTau pathology in the brain. In contrast, subretinally injected AD brain lysates accelerated pTau pathology in the retina and the contralateral superior colliculus. Subretinal injection of AD brain lysates, but not of non-AD brain, induced in this context a neuroinflammatory response in the retina and in the contralateral primary visual cortex. These results lead to the following conclusions: (1) Brain lysates from AD and non-AD sources can accelerate tauopathy within the retina. (2) The anterograde propagation of pTau pathology from the retina to the brain can be triggered by subretinal injections of AD brain lysates. (3) Such subretinal injections also provoke a neuroinflammatory response in both the retina and the visual cortex. (4) The accumulation of retinal pTau is associated with the degeneration of the involved ganglion cells, indicating that retinal tauopathy might contribute to vision impairment in the elderly and underscore the retina’s potential role in spreading tau pathology to the brain.

Delirium is a neuropsychiatric syndrome that is pathophysiologically related to both mental (dementia, depression) and physical illness. Its occurrence results in a poor prognosis. This study investigates whether specific miRNAs (miR-9-3p, miR-34c-5p, miR-96-5p, miR-183-5p, and miR-374-3p) related to brain function are associated with an increased risk of postoperative delirium. A total of 224 adult individuals scheduled for elective cardiac surgery were eligible to participate in the study. Delirium diagnosis was established with the use of the Confusion Assessment Method. Following miRNA expression profiling, cDNA synthesis was conducted on the samples obtained one day before and the day after surgery, from 60 delirium patients and 60 randomly selected non-delirium individuals. Univariate comparisons revealed that preoperative miR-96-5p (p = 0.05) and miR-183-5p (p = 0.001), along with postoperative miR-34c-5p (p = 0.009), miR-96-5p (p = 0.07), and miR-183-5p (p = 0.05), were associated with the risk of post-surgery delirium. However, after conducting multivariate logistic regression analysis, only miR-183-5p was found to be independently associated with the risk of delirium development. Other predictors of delirium included an ongoing episode of depression, peripheral vascular disease, female gender, active smoking, and increased postoperative pCO2 concentration. The current study revealed that preoperatively decreased expression of miR-183-5p predicts delirium development after cardiac surgery.

Tauopathy, including Alzheimer's Disease, is the most prevalent neurodegenerative disorder, yet current therapies fail to halt disease progression, partly due to limited understanding of early Tau pathological structures. Cryo-electron microscopy has clarified distinct Tau structures tied to disease phenotypes, but only in their mature forms and at low throughput. Hence, molecular probes that can recognize early Tau conformations in high throughput and in situ hold the potential to transform our understanding of Tau aggregation. Tau undergoes sequential changes, including hyperphosphorylation and misfolding, with the aggregation-prone PHF6 region in R3 shown to drive its self-assembly and fibrillar core formation. In this study, we used existing and novel monoclonal antibodies (mAbs) to map the Tau protein in AD and other Tauopathies. The conformation-specific antibody 16B12, targeting the R1-R3 regions, showed high sensitivity in detecting early Tau structures and inhibited seed-induced aggregation in vitro. Another antibody, 9H6F2, detected P1-P2 interactions and functioned as a pan-biomarker across Tauopathies. Our findings underscore the critical role of early P1-P2 and R1-R3 interactions in Tau fibril maturation, and our mAbs show promise as early diagnostic markers for Tau-related neurodegeneration.

Background: Pathogenic processes characteristic of neurodegenerative brain diseases, such as accumulation of phosphorylated Tau protein (pTau), can also be detected in the retina. Given the advanced state of retinal imaging technology and its potential to aid in the clinical diagnosis of Alzheimer’s disease (AD), it is imperative to investigate the part the retina plays in neurodegenerative diseases of the brain, as well as the associated eye‐specific degenerative processes.Methods: Retinas from 129 individuals who underwent eyeball resection/evisceration for severe ophthalmological conditions and from 35 post‐mortem donors with or without AD were analyzed. Paraffin‐embedded sections from cross‐sectioned retinas were stained with antibodies against different pTau species and Gallyas staining to detect neurofibrillary tangles. Retinal pTau accumulation, its distribution over the retinal layers, and molecular composition were determined neuropathologically and correlated with visual performance, age, and the presence of dementia.Results: Retinal pTau pathology showed a consistent topographical expansion pattern that allowed distinguishing four stages: Stage 0: no pTau pathology; Stage 1: thread‐like pTau in the outer plexiform layer; Stage 2: additional cytoplasmic pTau in the inner nuclear layer; Stage 3: thread‐like pTau also in the inner plexiform layers. Antibodies against pTau^S202/pT205 (AT8), pTau^T231 (AT180), and anti‐MC‐1 Tau showed comparable results. Neurofibrillary tangles were not found. The stage of retinal tauopathy was correlated with age (r = 0.176, p = 0.024, n = 164), the underlying ophthalmologic diseases (p = 0.001; β = 0.292), and independently associated with vision impairment (p = 0.030; β = 0.192) in a linear regression model. Cases with a clinical diagnosis of dementia were associated with slightly higher stages of retinal tauopathy (binary logistic regression: p = 0.026; odds ratio (OR) = 1.685 [95% C.I.1.066‐2.664), although some demented cases were free of pTau pathology.Conclusions: These results point towards the existence of a primary retinal tauopathy (PReT). It differs in its molecular composition from cerebral tauopathies by the lack of argyrophilic inclusions and the predominance of 3‐repeat Tau. However, PReT may be a prerequisite for developing AD pathology in the retina. Altogether, these findings support the presence of retinal neurodegenerative changes that may reflect changes in the brain.Funding: SAO/FRA 2020/017

BioStudies – one package for all the data supporting a study

Background: Delirium is a neuropsychiatric syndrome that is pathophysiologically related to both mental (dementia, depression) and physical illness. Its occurrence results in a poor prognosis. Specific miRNAs play a role in regulating central nervous system development, neuroinflammation, and neurodegeneration. This study investigates whether specific miRNAs (miR-9-3p, miR-34c-5p, miR-96-5p, miR-183-5p, and miR-374-3p) related to brain function are associated with an increased risk of postoperative delirium. Methods: A total of 224 adult individuals scheduled for elective cardiac surgery were eligible to participate in the study. Prior to surgery, each patient underwent psychiatric evaluation to identify major depressive disorder based on the DSM-5 criteria. Delirium diagnosis was established with the use of the Confusion Assessment Method. Following miRNA expression profiling, cDNA synthesis was conducted on 60 delirium patients and 60 randomly selected non-delirium individuals. MiRNA dqPCR analysis was performed on the serum samples obtained one day before and the day after surgery. Results: Of the 177 patients finally included, 34% (61 cases) experienced delirium. Univariate comparisons revealed that preoperative miR-96-5p (p=0.05) and miR-183-5p (p=0.001), along with postoperative miR-34c-5p (p=0.009), miR-96-5p (p=0.07), and miR-183-5p (p=0.05), were associated with the risk of post-surgery delirium. However, after conducting multivariate logistic regression analysis, only miR-183-5p was found to be independently associated with the risk of delirium development. Other predictors of delirium included an ongoing episode of depression, peripheral vascular disease, female gender, active smoking, and increased postoperative pCO2 concentration. Conclusion: The current study revealed that preoperatively decreased expression of miR-183-5p predicts delirium development after cardiac surgery.