Astrocytes associate with amyloid plaques in Alzheimer's disease (AD). Astrocytes react to changes in the brain environment, including increasing concentrations of amyloid‐β (Aβ). However, the precise response of astrocytes to soluble small Aβ oligomers at concentrations similar to those present in the human brain has not been addressed. In this study, we exposed astrocytes to media from neurons that express the human amyloid precursor protein (APP) transgene with the double Swedish mutation (APPSwe), and which contains APP‐derived fragments, including soluble human Aβ oligomers. We then used proteomics to investigate changes in the astrocyte secretome. Our data show dysregulated secretion of astrocytic proteins involved in the extracellular matrix and cytoskeletal organization and increase secretion of proteins involved in oxidative stress responses and those with chaperone activity. Several of these proteins have been identified in previous transcriptomic and proteomic studies using brain tissue from human AD and cerebrospinal fluid (CSF). Our work highlights the relevance of studying astrocyte secretion to understand the brain response to AD pathology and the potential use of these proteins as biomarkers for the disease.

No abstract

Image denoising, a fundamental step in image processing, has been widely studied for several decades. Denoising methods can be classified as internal or external depending on whether they exploit the internal prior or the external noisy-clean image priors to reconstruct a latent image. Typically, these two kinds of methods have their respective merits and demerits. Using a single denoising model to improve existing methods remains a challenge. In this paper, we propose a method for boosting the denoising effect via the image fusion strategy. This study aims to boost the performance of two typical denoising methods, the nonlocally centralized sparse representation (NCSR) and residual learning of deep CNN (DnCNN). These two methods have complementary strengths and can be chosen to represent internal and external denoising methods, respectively. The boosting process is formulated as an adaptive weight-based image fusion problem by preserving the details for the initial denoised images output by the NCSR and the DnCNN. Specifically, we design two kinds of weights to adaptively reflect the influence of the pixel intensity changes and the global gradient of the initial denoised images. A linear combination of these two kinds of weights determines the final weight. The initial denoised images are integrated into the fusion framework to achieve our denoising results. Extensive experiments show that the proposed method significantly outperforms the NCSR and the DnCNN both quantitatively and visually when they are considered as individual methods; similarly, it outperforms several other state-of-the-art denoising methods.

Background Molecular chaperones have protective functions in neurodegeneration by preventing misfolding of aggregation‐prone proteins. These functions have been mostly studied in neurons. However, members of the family of chaperones known as small heat shock proteins (sHSPs), including HSPB1, CRYAB, and HSPB8, are specifically expressed in glial cells rather than in neurons, and their levels increase in astrocytes in human post‐mortem Alzheimer’s disease (AD) brain. While traditionally considered intracellular proteins, novel extracellular functions have been attributed to chaperones in cancer or the immune system. Interestingly, HSPB1 is also found in senile plaques suggesting these can also be extracellular in the brain. We hypothesize that sHSP can be extracellular and aim to investigate whether sHSPs are secreted from astrocytes in Alzheimer’s disease brain. Method We used human post‐mortem brain sections from Alzheimer’s disease patients to investigate changes in extracellular/intracellular localization of HSPB1. To further explore sHSPs secretion, we used primary mouse astrocytes. Reactive astrocytes were induced by TNFα and IL‐1α, mimicking the local environment in the diseased brain. We investigated changes in astrocyte cell lysates and the astrocyte conditioned media by Western blot. To investigate the secretion mechanisms, we also use size exclusion chromatography (SEC) and nanoparticle tracking analysis (NTA) Result Although sHSPs are intracellular chaperones, Our analysis of AD patients post‐mortem brain sections suggested that extracellular HSPB1 might increase around astrocytes that are close to amyloid plaques. In primary mouse astrocytes, we also found an increase in sHSPs in the extracellular media when astrocytes become reactive upon treatment with TNFα and IL‐1α. We further investigated their mechanism of secretion by fractionating the astrocyte conditioned media using SEC. NTA and proteinase K protection assays show that the sHSPs were not present in extracellular vesicle fractions, but rather free in the media. Conclusion Our study suggests that HSPB1 is secreted from astrocytes near to plaques in AD brain, as well as from reactive astrocytes in culture, and this secretion is not dependent on extracellular vesicles. The mechanisms behind how sHSPs are secreted and their extracellular functions still need to be explored.

Background Astrocytes are vital in the onset and progression of Alzheimer’s disease (AD). Accumulation of reactive astrocytes, together with tau phosphorylation, correlates very strongly with cognitive decline. Molecular chaperones are essential for maintaining protein homeostasis. One family of chaperones are the small heat shock proteins (sHSPs), which include HSPB1 and CRYAB. Expression of these sHSPs seems to be restricted to glial cells, and levels are found to increase in those astrocytes found in AD brains. The role that sHSP play in astrocytes in AD is still not known. Emerging evidence suggests vital interplay between different cell types during neurodegenerative diseases. We therefore aim to investigate the non‐cell autonomous role of astrocytic sHSPs in AD. Method We are using primary mouse neurons and organotypic brain slice cultures in conjunction with the recombinant adeno‐associated viral system (rAAV). These systems will allow us to replicate the tau pathology found in AD, investigate neuron‐astrocyte interactions and determine whether either can be altered by overexpression of our sHSPs. Using immunofluorescence, confocal microscopy and western blotting we are characterising expression and localization of sHSPs in post‐mortem human AD brain tissue and brain slice cultures. Result Our data shows that HSPB1 is specifically expressed in astrocytes in both human brain tissue and slice cultures. Interestingly, HSPB1 levels in the human brain increase in GFAP‐positive astrocytes surrounding amyloid plaques. When organotypic brain slices are treated with cytokines or Aβ oligomers, reactive astrocytes are induced and levels of HSPB1 and CRYAB are also increased, similar to what we observe in human AD brain. Conclusion Our results in human AD brain highlight the importance of astrocytic HSPB1 in AD, and we provide evidence to suggest not only that organotypic brain slices are a good model to replicate and study the function of sHSPs in AD, but that HSPB1 and CRYAB play an important role in the response to AD‐relevant pathology. Using rAAVs, we aim to manipulate astrocytic sHSPs levels in organotypic brain slices to investigate whether astrocytic sHSPs could modulate neuronal health and tau pathology in a non‐cell autonomous manner.