Beneficial Effect of ACI-24 Vaccination on Aß Plaque Pathology and Microglial Phenotypes in an Amyloidosis Mouse Model.

Amyloid-ß (Aß) deposition is an initiating factor in Alzheimer's disease (AD). Microglia are the brain immune cells that surround and phagocytose Aß plaques, but their phagocytic capacity declines in AD. This is in agreement with studies that associate AD risk loci with genes regulating the phagocytic function of immune cells. Immunotherapies are currently pursued as strategies against AD and there are increased efforts to understand the role of the immune system in ameliorating AD pathology. Here, we evaluated the effect of the Aß targeting ACI-24 vaccine in reducing AD pathology in an amyloidosis mouse model. ACI-24 vaccination elicited a robust and sustained antibody response in APPPS1 mice with an accompanying reduction of Aß plaque load, Aß plaque-associated ApoE and dystrophic neurites as compared to non-vaccinated controls. Furthermore, an increased number of NLRP3-positive plaque-associated microglia was observed following ACI-24 vaccination. In contrast to this local microglial activation at Aß plaques, we observed a more ramified morphology of Aß plaque-distant microglia compared to non-vaccinated controls. Accordingly, bulk transcriptomic analysis revealed a trend towards the reduced expression of several disease-associated microglia (DAM) signatures that is in line with the reduced Aß plaque load triggered by ACI-24 vaccination. Our study demonstrates that administration of the Aß targeting vaccine ACI-24 reduces AD pathology, suggesting its use as a safe and cost-effective AD therapeutic intervention.

Fibrillar Aß triggers microglial proteome alterations and dysfunction in Alzheimer mouse models.

Microglial dysfunction is a key pathological feature of Alzheimer's disease (AD), but little is known about proteome-wide changes in microglia during the course of AD and their functional consequences. Here, we performed an in-depth and time-resolved proteomic characterization of microglia in two mouse models of amyloid ß (Aß) pathology, the overexpression APPPS1 and the knock-in APP-NL-G-F (APP-KI) model. We identified a large panel of Microglial Aß Response Proteins (MARPs) that reflect heterogeneity of microglial alterations during early, middle and advanced stages of Aß deposition and occur earlier in the APPPS1 mice. Strikingly, the kinetic differences in proteomic profiles correlated with the presence of fibrillar Aß, rather than dystrophic neurites, suggesting that fibrillar Aß may trigger the AD-associated microglial phenotype and the observed functional decline. The identified microglial proteomic fingerprints of AD provide a valuable resource for functional studies of novel molecular targets and potential biomarkers for monitoring AD progression or therapeutic efficacy.

Alzheimer's disease is a progressive, irreversible brain disorder. Patients with Alzheimer's have problems with memory and other mental skills, which lead to more severe cognitive decline and, eventually, premature death. This is due to increasing numbers of nerve cells in the brain dying over time. A distinctive feature of Alzheimer's is the abnormally high accumulation of a protein called amyloid-ß, which forms distinctive clumps in the brain termed 'plaques'. The brain has a type of cells called the microglia that identify infections, toxic material and damaged cells, and prevent these from building up by clearing them away. In Alzheimer's disease, however, the microglia do not work properly, which is thought to contribute to the accumulation of amyloid-ß plaques. This means that people with mutations in the genes important for the microglia activity are also at higher risk of developing the disease. Although problems with the microglia play an important role in Alzheimer's, researchers still do not fully understand why microglia stop working in the first place. It is also not known exactly when and how the microglia change as Alzheimer's disease progresses. To unravel this mystery, Sebastian Monasor, Müller et al. carried out a detailed study of the molecular 'fingerprints' of microglia at each key stage of Alzheimer's disease. The experiments used microglia cells from two different strains of genetically altered mice, both of which develop the hallmarks of Alzheimer's disease, including amyloid-ß plaques, at similar rates. Analysis of the proteins in microglia cells from both strains revealed distinctive, large-scale changes corresponding to successive stages of the disease ­ reflecting the gradual accumulation of plaques. Obvious defects in microglia function also appeared soon after plaques started to build up. Microscopy imaging of the brain tissue showed that although amyloid-ß plaques appeared at the same time, they looked different in each mouse strain. In one, plaques were more compact, while in the other, plaques appeared 'fluffier', like cotton wool. In mice with more compacted plaques, microglia recognized the plaques earlier and stopped working sooner, suggesting that plaque structure and microglia defects could be linked. These results shed new light on the role of microglia and their changing protein 'signals' during the different stages of Alzheimer's disease. In the future, this information could help identify people at risk for the disease, so that they can be treated as soon as possible, and to design new therapies to make microglia work again.