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Reduction of amyloid beta (Aβ) has been shown to be effective in treating Alzheimer’s disease (AD), but the underlying assumption that neurons are the main source of pathogenic Aβ is untested. Here, we challenge this prevailing belief by demonstrating that oligodendrocytes are an important source of Aβ in the human brain and play a key role in promoting abnormal neuronal hyperactivity in an AD knock-in mouse model. We show that selectively suppressing oligodendrocyte Aβ production improves AD brain pathology and restores neuronal function in the mouse model in vivo. Our findings suggest that targeting oligodendrocyte Aβ production could be a promising therapeutic strategy for treating AD.

Reduced insulin-like growth factor 2 (IGF2) levels in Alzheimer’s disease (AD) may be the mechanism relating age-related metabolic disorders to dementia. Since Igf2 is an imprinted gene, we examined age and sex differences in the relationship between amyloid-beta 1–42 ( Aβ 42 ) accumulation and epigenetic regulation of the Igf2/H19 gene cluster in cerebrum, liver, and plasma of young and old male and female 5xFAD mice, in frontal cortex of male and female AD and non-AD patients, and in HEK293 cell cultures. We show IGF2 levels, Igf2 expression, histone acetylation, and H19 ICR methylation are lower in females than males. However, elevated Aβ 42 levels are associated with Aβ 42 binding to Igf2 DMR2, increased DNA and histone methylation, and a reduction in Igf2 expression and IGF2 levels in 5xFAD mice and AD patients, independent of H19 ICR methylation. Cell culture results confirmed the binding of Aβ 42 to Igf2 DMR2 increased DNA and histone methylation, and reduced Igf2 expression. These results indicate an age- and sex-related causal relationship among Aβ 42 levels, epigenomic state, and Igf2 expression in AD and provide a potential mechanism for Igf2 regulation in normal and pathological conditions, suggesting IGF2 levels may be a useful diagnostic biomarker for Aβ 42 targeted AD therapies.

Mouse models of Alzheimer's disease (AD) exhibit marked differences in life expectancy depending on their genotype and sex. The assessment of frailty could provide a measure of healthspan to facilitate comparisons between different AD models. We used a validated mouse frailty index (FI) assessment tool to explore genotype and sex differences in lifespan and healthspan of 3xTg-AD mice and their B6129F2 wild-type (WT) controls. This tool is based on an approach commonly used in people and quantifies frailty by counting the accumulation of age-related health deficits. The number of deficits in an individual divided by the total number measured yields an FI score theoretically between 0 and 1, with higher scores denoting more frailty. Male 3xTg-AD mice aged 300-600 days had higher FI scores (Mean FI = 0.21 ± 0.03) than either male WT (Mean FI = 0.15 ± 0.01) or female 3xTg-AD mice (Mean FI = 0.10 ± 0.01), and the elevated frailty scores were accompanied by parallel increases in mortality. Frailty increased exponentially with age, and higher rates of deficit accumulation elevated mortality risk in all groups of mice. When mice were stratified by FI score, frailty predicted mortality, at least in females. Therefore, the mouse clinical FI provides a valuable tool for evaluating healthspan in mouse models of AD with different lifespans.

The kynurenine pathway metabolizes tryptophan into nicotinamide adenine dinucleotide, producing a number of intermediary metabolites, including 3-hydroxy kynurenine and quinolinic acid, which are involved in the neurodegenerative mechanisms that underlie Alzheimer’s disease (AD). Indolamine 2,3-dioxygenase (IDO), the first and rate-limiting enzyme of this pathway, is increased in AD, and it has been hypothesized that blocking this enzyme may slow the progression of AD. In this study, we treated male and female 3xTg-AD and wild-type mice with the novel IDO inhibitor DWG-1036 (80 mg/kg) or vehicle (distilled water) from 2 to 6 months of age and then tested them in a battery of behavioral tests that measured spatial learning and memory (Barnes maze), working memory (trace fear conditioning), motor coordination and learning (rotarod), anxiety (elevated plus maze), and depression (tail suspension test). The 3xTg-AD mice treated with DWG-1036 showed better memory in the trace fear conditioning task and significant improvements in learning but poorer spatial memory in the Barnes maze. DWG-1036 treatment also ameliorated the behaviors associated with increased anxiety in the elevated plus maze and depression-like behaviors in the tail suspension test in 3xTg-AD mice. However, the effects of DWG-1036 treatment on the behavioral tasks were variable, and sex differences were apparent. In addition, high doses of DWG-1036 resulted in reduced body weight, particularly in females. Taken together, our results suggest that the kynurenine pathway is a promising target for treating AD, but more work is needed to determine the effective compounds, examine sex differences, and understand the side effects of the compounds.

Background The tumour-suppressor protein p53 can form amyloid aggregates resulting in loss of tumour-suppressing functions and leading to tumour formation. The detection of p53 aggregates in cancer cells has been demonstrated but these aggregates have not been detected in liquid biopsies to date, due to the lack of sufficiently sensitive methods. Methods We developed an ultrasensitive immunoassay based on the single-molecule array (SiMoA) technology to detect p53 aggregates in plasma, based on antibody capture of the aggregates. We confirmed that the assay detects p53 aggregates using super-resolution imaging. We then investigated the p53 aggregate concentrations in the plasma of 190 pre-surgery glioblastoma (GB) patients and 22 controls using this assay. Results We found that the plasma p53 aggregate levels are significantly elevated in pre-surgery GB patients’ plasma compared to controls. Longitudinal study further reveals that p53 aggregate levels may increase before GB recurrence and decrease following treatment. We also observed raised p53 aggregate concentrations in the plasma of cancer patients with brain metastases. Conclusions This study demonstrates the detection of p53 aggregates in liquid biopsies. Our findings highlight the potential of p53 aggregates as a novel biomarker for glioblastoma. Wu et al. develop an ultrasensitive immunoassay based on the single-molecule array (SiMoA) technology to detect p53 aggregates in plasma. They show that the p53 aggregate concentrations in the plasma of pre-surgery glioblastoma patients are significantly higher compared to controls. Plain language summary p53 is an important protein molecule that prevents cancer from developing. However, under some conditions, p53 can clump together to form aggregates. These aggregates cannot stop cancer and may even help cancer grow. This makes p53 aggregates a potential marker of cancer. We have developed a very sensitive test to catch and detect the rare p53 aggregates in the blood. With this test, we find that there are more p53 aggregates in the blood of glioblastoma (a highly aggressive brain cancer) patients than people without cancer. Our test is 90.57% accurate in diagnosing glioblastoma and may also help predict cancer recurrence and monitor treatment response.

INTRODUCTION Beta‐amyloid plaques and hyperphosphorylated tau tangles are the neuropathological hallmarks of Alzheimer's disease; however, their relevance in the pathophysiology is not fully understood. It has been suggested that these larger and insoluble aggregates may not be the most toxic forms of beta‐amyloid and tau in Alzheimer's disease, and the disease progression may actually be promoted by the small‐diffusible aggregates. METHODS AND RESULTS We combine the recent findings from our group and other key research to put forward the hypotheses that the formation of the small‐diffusible aggregates of beta‐amyloid and tau and their larger insoluble counterparts is not a linear process. DISCUSSION While the small‐diffusible aggregate formation of beta‐amyloid and tau is a passive process, regulated by thermodynamic equilibria, the formation of large‐insoluble aggregates is an active process, regulated by microglia and neurons, which to an extent is a protective mechanism against the toxicity of the smaller aggregates. Highlights Plaques and tangles may be made by active processes in Alzheimer's disease. The small‐soluble aggregates may be the more toxic species in Alzheimer's disease. Pathology may be caused by the imbalance of production and clearance of aggregates. Plaques and tangle formation may be attempts to restore the homeostatic equilibrium.

INTRODUCTION The monoclonal antibodies Aducanumab, Lecanemab, Gantenerumab, and Donanemab were developed for the treatment of Alzheimer's disease (AD). METHODS We used single‐molecule detection and super‐resolution imaging to characterize the binding of these antibodies to diffusible amyloid beta (Aβ) aggregates generated in‐vitro and harvested from human brains. RESULTS Lecanemab showed the best performance in terms of binding to the small‐diffusible Aβ aggregates, affinity, aggregate coating, and the ability to bind to post‐translationally modified species, providing an explanation for its therapeutic success. We observed a Braak stage–dependent increase in small‐diffusible aggregate quantity and size, which was detectable with Aducanumab and Gantenerumab, but not Lecanemab, showing that the diffusible Aβ aggregates change with disease progression and the smaller aggregates to which Lecanemab preferably binds exist at higher quantities during earlier stages. DISCUSSION These findings provide an explanation for the success of Lecanemab in clinical trials and suggests that Lecanemab will be more effective when used in early‐stage AD. Highlights Anti amyloid beta therapeutics are compared by their diffusible aggregate binding characteristics. In‐vitro and brain‐derived aggregates are tested using single‐molecule detection. Lecanemab shows therapeutic success by binding to aggregates formed in early disease. Lecanemab binds to these aggregates with high affinity and coats them better.

Understanding the role of small, soluble aggregates of beta-amyloid (Aβ) and tau in Alzheimer’s disease (AD) is of great importance for the rational design of preventative therapies. Here we report a set of methods for the detection, quantification, and characterisation of soluble aggregates in conditioned media of cerebral organoids derived from human iPSCs with trisomy 21, thus containing an extra copy of the amyloid precursor protein (APP) gene. We detected soluble beta-amyloid (Aβ) and tau aggregates secreted by cerebral organoids from both control and the isogenic trisomy 21 (T21) genotype. We developed a novel method to normalise measurements to the number of live neurons within organoid-conditioned media based on glucose consumption. Thus normalised, T21 organoids produced 2.5-fold more Aβ aggregates with a higher proportion of larger (300–2000 nm 2 ) and more fibrillary-shaped aggregates than controls, along with 1.3-fold more soluble phosphorylated tau (pTau) aggregates, increased inflammasome ASC-specks, and a higher level of oxidative stress inducing thioredoxin-interacting protein (TXNIP). Importantly, all this was detectable prior to the appearance of histological amyloid plaques or intraneuronal tau-pathology in organoid slices, demonstrating the feasibility to model the initial pathogenic mechanisms for AD in-vitro using cells from live genetically pre-disposed donors before the onset of clinical disease. Then, using different iPSC clones generated from the same donor at different times in two independent experiments, we tested the reproducibility of findings in organoids. While there were differences in rates of disease progression between the experiments, the disease mechanisms were conserved. Overall, our results show that it is possible to non-invasively follow the development of pathology in organoid models of AD over time, by monitoring changes in the aggregates and proteins in the conditioned media, and open possibilities to study the time-course of the key pathogenic processes taking place.

Alzheimer's disease is the most frequent form of dementia in elderly people. The triple transgenic (3xTg‐AD) mouse model of Alzheimer's Disease is important in biomedical research as these mice develop both neuropathological and behavioural phenotypes. However, their behavioural phenotype is variable, with findings depending on the specific task, as well as the age and sex of the mice. Whisker movements show motor, sensory and cognitive deficits in mouse models of neurodegenerative disease. Therefore, we examined whisker movements in 3, 12.5 and 17‐month‐old female 3xTg‐AD mice and their B6129S/F2 wildtype controls. Mice were filmed using a high‐speed video camera (500 fps) in an open arena during a novel object exploration task. Genotype and age differences were found in mice exploring the arena prior to object contact. Prior to whisker contact, the 3‐month‐old 3xTg‐AD mice had smaller whisker angles compared with the wildtype controls, suggesting an early motor phenotype in these mice. Pre‐contact mean angular position at 3 months and whisking amplitude at 17 months of age differed between the 3xTg‐AD and wildtype mice. During object contact 3xTg‐AD mice did not reduce whisker spread as frequently as the wildtype mice at 12.5 and 17 months, which may suggest sensory or attentional deficits. We show that whisker movements are a powerful behavioural measurement tool for capturing behavioural deficits in mouse models that show complex phenotypes, such as the 3xTg‐AD mouse model. Genotype and age differences were found in 3xTg‐AD mice exploring the arena prior to and during object contact, suggesting an early motor phenotype and sensory or attentional deficits in 3xTg‐AD mouse model. Whisker movements are a powerful behavioural measurement tool for capturing behavioural deficits in mouse models that show complex phenotypes.