Evaluating the inter-species transmission risk of amyloid beta peptide aggregates via ingestion.

BACKGROUND: Recent reports suggest that amyloid beta (Aß) peptides can exhibit prion-like pathogenic properties. Transmission of Aß peptide and the development of associated pathologies after surgeries with contaminated instruments and intravenous or intracerebral inoculations have now been reported across fish, rodents, primates, and humans. This raises a worrying prospect of Aß peptides also having other characteristics typical of prions, such as evasion of the digestive process. We asked if such transmission of Aß aggregates via ingestion was possible. METHODS: We made use of a transgenic Drosophila melanogaster line expressing human Aß peptide prone to aggregation. Fly larvae were fed to adult zebrafish under two feeding schemes. The first was a short-term, high-intensity scheme over 48 h to determine transmission and retention in the gut. The second, long-term scheme specifically examined retention and accumulation in the brain. The gut and brain tissues were examined by histology, western blotting, and mass spectrometric analyses. RESULTS: None of the analyses could detect Aß aggregates in the guts of zebrafish following ingestion, despite being easily detectable in the feed. Additionally, there was no detectable accumulation of Aß in the brain tissue or development of associated pathologies after prolonged feeding. CONCLUSIONS: While human Aß aggregates do not appear to be readily transmissible by ingestion across species, two prospects remain open. First, this mode of transmission, if occurring, may stay below a detectable threshold and may take much longer to manifest. A second possibility is that the human Aß peptide is not able to trigger self-propagation or aggregation in other species. Either possibility requires further investigation, taking into account the possibility of such transmission from agricultural species used in the food industry.

Identifying Brain Connectivity Using Network-Based Statistics in Amnestic Mild Cognitive Impairment Stratified by ß-Amyloid Positivity.

BACKGROUND: The aim of this study was to identify white matter structural networks of amnestic mild cognitive impairment (aMCI) dichotomized by ß amyloid (Aß) status and compare them using network-based statistics (NBS). METHODS: Patients underwent whole-brain diffusion-weighted magnetic resonance imaging, detailed neuropsychological test and [18F]-Florbetaben amyloid positron emission tomography. We performed the NBS analysis to compare the whole-brain white matter structural networks extracted from diffusion tensor images. RESULTS: One hundred sixteen participants (Aß- cognitively normal [CN], n = 35; Aß- aMCI, n = 42; Aß+ aMCI, n = 39) were included. There was no subnetwork showing significant difference between Aß+ aMCI and Aß- aMCI. However, by comparing each aMCI group with control group, we found that supplementary motor areas were common hub regions. Intriguingly, Aß+ aMCI showed reduced connectivity mainly in the medial frontal regions, while Aß- aMCI showed somewhat uniform disruption when compared to CN. CONCLUSION: Structural network analysis using network-based approach in aMCI may shed light on further understanding of white matter disruption in the prodromal stage of Alzheimer's disease.

Proamyloidogenic effects of membrane type 1 matrix metalloproteinase involve MMP-2 and BACE-1 activities, and the modulation of APP trafficking.

We previously demonstrated that membrane type 1 (MT1) matrix metalloproteinase (MMP) was up-regulated in the hippocampus of the model of transgenic mice bearing 5 familial mutations on human amyloid precursor protein (APP) and presenilin 1 of Alzheimer disease (AD), and that the proteinase increased the levels of amyloid ß peptide (Aß) and its APP C-terminal fragment of 99 aa in a heterologous cell system. Here we provide further evidence that MT1-MMP interacts with APP and promotes amyloidogenesis in a proteolytic-dependent manner in Swedish APP-expressing human embryonic kidney 293 (HEKswe) cells. MT1-MMP-mediated processing of APP releases a soluble APP fragment, sAPP95. This process partly requires the activation of endogenous MMP-2 but is independent of ß-site APP cleaving enzyme 1 (BACE-1) or α-secretase activities. In contrast, MT1-MMP-mediated increase of Aß levels involved BACE-1 activity and was inhibited by tissue inhibitor of MMP-2, a natural inhibitor of both MT1-MMP and MMP-2. Interestingly, near abolishment of basal Aß production upon BACE-1 inhibition was rescued by MT1-MMP, indicating that the latter could mimic ß-secretase-like activity. Moreover, MT1-MMP promoted APP/Aß localization in endosomes, where Aß production mainly occurs. These data unveil new mechanistic insights to support the proamyloidogenic role of MT1-MMP based on APP processing and trafficking, and reinforce the idea that this proteinase may become a new potential therapeutic target in AD.-Paumier, J.-M., Py, N. A., González, L. G., Bernard, A., Stephan, D., Louis, L., Checler, F., Khrestchatisky, M., Baranger, K., Rivera, S. Proamyloidogenic effects of membrane type 1 matrix metalloproteinase involve MMP-2 and BACE-1 activities, and the modulation of APP trafficking.

Mechanistic comparison of current pharmacological treatments and novel phytochemicals to target amyloid peptides in Alzheimer's and neurodegenerative diseases.

The formation of ß amyloid plaques is one of the pathological hallmarks of Alzheimer's disease (AD). The process of accumulation of extracellular deposits of amyloid plaques occurs by the abnormal proteolysis of amyloid precursor protein, resulting in the formation of ß amyloid peptides which further aggregates and results in the formation of oligomers, protofibrils, fibrils, and plaques. The complexity in understanding the aggregation process has provided avenues for identifying potential targets against amyloid toxicity in the treatment of AD. The therapeutic approach mainly focuses on reducing the toxicity by halting the ß amyloid fibril formation. Besides conventional medicine, several naturally available compounds were shown to reduce the toxicity of amyloid plaques in the current scenario. This review provides a comprehensive account on recent updates of FDA-approved and naturally available compounds against toxicity of amyloid peptides and plaques both in vitro and in vivo.

Lessons from Anti-Amyloid-ß Immunotherapies in Alzheimer Disease: Aiming at a Moving Target.

BACKGROUND: Available drugs for the global Alzheimer disease (AD) epidemic only treat the symptoms without modifying disease progression. Accumulating evidence supports amyloid-ß42 (Aß42)as the key triggering agent in AD, making it the ideal target for disease-modifying therapies. Preclinical studies provided extensive support for passive Aß42 immunotherapy, leading to human clinical trials with different antibodies. OBJECTIVE: Examine the status of clinical trials for passive immunotherapy against Aß42. METHODS: We performed a thorough literature review of passive Aß42 immunotherapy. RESULTS: Ten anti-Aß42 antibodies targeting lineal or conformational epitopes have been tested in clinical trials. Antibody engineering and appropriate dosing have overcome undesired side effects, leading to increased safety profiles. Unfortunately, few trials have shown cognitive protection, leading to legitimate questions about the utility of Aß42 as an AD target. There is still hope that solanezumab, aducanumab, and other ongoing trials will identify antibodies, patient subpopulations, and administration protocols, with consistent clinical benefits. CONCLUSIONS: Despite the overall disappointing results, there is still hope that Aß immunotherapy in presymptomatic patients will prevent neuronal loss and provide significant clinical benefits that can be applied to larger populations as preventive therapies. Advances with other targets may soon provide additional therapeutic options for AD with increased efficacy.

Effect of metal chelators on the aggregation of beta-amyloid peptides in the presence of copper and iron.

Amyloid ß (Aß) fibrils and amorphous aggregates are found in the brain of patients with Alzheimer's disease (AD), and are implicated in the etiology of AD. The metal imbalance is also among leading causes of AD, owing to the fact that Aß aggregation takes place in the synaptic cleft where Aß, Cu(II) and Fe(III) are found in abnormally high concentrations. Aß40 and Aß42 are the main components of plaques found in afflicted brains. Coordination of Cu(II) and Fe(III) ions to Aß peptides have been linked to Aß aggregation and production of reactive oxygen species, two key events in the development of AD pathology. Metal chelation was proposed as a therapy for AD on the basis that it might prevent Aß aggregation. In this work, we first examined the formation of Aß40 and Aß42 aggregates in the presence of metal ions, i.e. Fe(III) and Cu(II), which were detected by fluorescence spectroscopy and atomic force microscopy. Second, we studied the ability of the two chelators, ethylenediaminetetraacetic acid and 5-chloro-7-iodo-8-hydroxyquinoline (clioquinol), to investigate their effect on the availability of these metal ions to interact with Aß and thereby their effect on Aß accumulation. Our findings show that Fe(III), but not Cu(II), promote aggregation of both Aß40 and Aß42. We also found that only clioquinol decreased significantly iron ion-induced aggregation of Aß42. The presence of ions and/or chelators also affected the morphology of Aß aggregates.

Estrogen associated gene polymorphisms and their interactions in the progress of Alzheimer's disease.

The extensive neuroprotective effects of estrogen against Alzheimer's disease (AD) have been proven in numerous laboratory studies. However, in clinical studies, the exact role of estrogen in AD is still ambiguous. Some evidences even suggested the high levels of estrogen or estrogen replacement treatment increased the risk of AD. Thus, there must be other factors affecting the neuroprotective effects of estrogen. Multiple enzymes and receptor proteins are involved in the biosynthesis, metabolism and signaling pathways of estrogen, and mediate the beneficial effects of estrogen on AD. Previous studies have suggested some polymorphisms of genes encoding these enzymes and proteins are associated with the risk of AD. In addition to the genes associated with estrogen biosynthesis and metabolism and the genes encoding estrogen receptor proteins, some other genes also modulate the effects of estrogen on AD, or interact with other estrogen-associated genes on the progress of AD. The gene-hormone and gene-gene interactions may be key to unraveling the conflicting results regarding the effect of estrogen on AD. In this paper, we will review and discuss the associations between polymorphisms of these genes and their interactions and the susceptibility to AD. A better understanding of these estrogen-associated genes is significant to explore the pathogenesis of AD.