Figure - available from: Current Neurology and Neuroscience Reports
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IgG isotypes, isomers, and FcγR affinities. A Four structures of IgG antibody subtypes characterized by variations in hinge disulfide bonds between the two heavy chains. (A’) Three of the IgG2 isomers characterized by the variations in heavy and light chain disulfide bonds. (A’’) Highlight of the regions where isotypes and hinges vary. B IgG isotypes identified by Fcγ receptor affinity. Figure created in BioRender.com
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Purpose of Review
Amyloid beta (Aβ) plaque accumulation is a hallmark pathology contributing to Alzheimer’s disease (AD) and is widely hypothesized to lead to cognitive decline. Decades of research into anti-Aβ immunotherapies provide evidence for increased Aβ clearance from the brain; however, this is frequently accompanied by complicated vascular...
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Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive neurodegeneration and cognitive decline. Evodiamine, a main component in Chinese medicine, was found to improve cognitive impairment in AD model mice based on several intensive studies. However, evodiamine has high cytotoxicity and poor bioactivity. In this study,...
Citations
... However, some patients who experienced more severe symptoms have been withdrawn from the clinical trials. There is a higher risk of developing this side effect for carriers of APOE-ε4 [53] and having two copies of this gene virtually guarantees the development of Alzheimer's at an earlier age [54,55]. ...
Antibodies that can selectively remove rogue proteins in the brain are an obvious choice to treat neurodegenerative disorders (NDs), but after decades of efforts, only two antibodies to treat Alzheimer’s disease are approved, dozens are in the testing phase, and one was withdrawn, and the other halted, likely due to efficacy issues. However, these outcomes should have been evident since these antibodies cannot enter the brain sufficiently due to the blood–brain barrier (BBB) protectant. However, all products can be rejuvenated by binding them with transferrin, preferably as smaller fragments. This model can be tested quickly and at a low cost and should be applied to bapineuzumab, solanezumab, crenezumab, gantenerumab, aducanumab, lecanemab, donanemab, cinpanemab, and gantenerumab, and their fragments. This paper demonstrates that conjugating with transferrin does not alter the binding to brain proteins such as amyloid-β (Aβ) and α-synuclein. We also present a selection of conjugate designs that will allow cleavage upon entering the brain to prevent their exocytosis while keeping the fragments connected to enable optimal binding to proteins. The identified products can be readily tested and returned to patients with the lowest regulatory cost and delays. These engineered antibodies can be manufactured by recombinant engineering, preferably by mRNA technology, as a more affordable solution to meet the dire need to treat neurodegenerative disorders effectively.
... This comparative approach using different types of Aβ species is required, given that modern therapies against AD are directed toward targeting Aβ peptides employing specific antibodies [58], as demonstrated by the recent US Food and Drug Administration approval of aducanumab as the first AD-specific treatment [59,60]. Despite the controversy regarding its efficacy, clinical trials reveal that the main undesired effects of this approach are related to enhanced vascular damage [61][62][63]. Particularly, evidence accumulated from murine models and clinical trials suggests that passive immunization with antibodies targeting fibrillar Aβ42 aggravates cerebral amyloid angiopathy in some patients, exacerbating vascular damage and brain edema [64][65][66]. This suggests that amyloid angiopathy should not be considered an event occurring independently of vascular alterations and that the interaction between both should be elucidated by basic studies to support future clinical studies. ...
Alzheimer’s disease (AD) is characterized by the accumulation of aggregated amyloid peptides in the brain parenchyma and within the walls of cerebral vessels. The hippocampus—a complex brain structure with a pivotal role in learning and memory—is implicated in this disease. However, there is limited data on vascular changes during AD pathological degeneration in this susceptible structure, which has distinctive vascular traits. Our aim was to evaluate vascular alterations in the hippocampus of AD patients and PDAPP-J20 mice—a model of AD—and to determine the impact of Aβ40 and Aβ42 on endothelial cell activation. We found a loss of physical astrocyte-endothelium interaction in the hippocampus of individuals with AD as compared to non-AD donors, along with reduced vascular density. Astrocyte-endothelial interactions and levels of the tight junction protein occludin were altered early in PDAPP-J20 mice, preceding any signs of morphological changes or disruption of the blood–brain barrier in these mice. At later stages, PDAPP-J20 mice exhibited decreased vascular density in the hippocampus and leakage of fluorescent tracers, indicating dysfunction of the vasculature and the BBB. In vitro studies showed that soluble Aβ40 exposure in human brain microvascular endothelial cells (HBMEC) was sufficient to induce NFκB translocation to the nucleus, which may be linked with an observed reduction in occludin levels. The inhibition of the membrane receptor for advanced glycation end products (RAGE) prevented these changes in HBMEC. Additional results suggest that Aβ42 indirectly affects the endothelium by inducing astrocytic factors. Furthermore, our results from human and mouse brain samples provide evidence for the crucial involvement of the hippocampal vasculature in Alzheimer’s disease.
INTRODUCTION
In September 2022, The Jackson Laboratory Center for Alzheimer's and Dementia Research (JAX CADR) hosted a workshop with leading researchers in the Alzheimer's disease and related dementias (ADRD) field.
METHODS
During the workshop, the participants brainstormed new directions to overcome current barriers to providing patients with effective ADRD therapeutics. The participants outlined specific areas of focus. Following the workshop, each group used standard literature search methods to provide background for each topic.
RESULTS
The team of invited experts identified four key areas that can be collectively addressed to make a significant impact in the field: (1) Prioritize the diversification of disease targets, (2) enhance factors promoting resilience, (3) de‐risk clinical pipeline, and (4) centralize data management.
DISCUSSION
In this report, we review these four objectives and propose innovations to expedite ADRD therapeutic pipelines.
Alzheimer's disease (AD) is characterized by the accumulation of aggregated amyloid peptides in the brain parenchyma and also around vasculature. The hippocampus -a complex brain structure with a crucial role in learning and memory- is considered a target in the pathology. However, there is scarce information regarding vascular changes during the AD neurodegenerative process in this vulnerable structure, that is a unique in terms of vasculature features. Our aim was to evaluate hippocampal vascular alterations in AD patients and PDAPP-J20 mice -model of AD- and define the impact of Aβ40 and Aβ42 on endothelial activation. We found loss of physical astrocyte-endothelium interaction in the hippocampus of AD subjects as compared to non-AD donors together with decreased vascular density. Astrocyte-endothelial interactions and levels of the tight junction protein occludin were early altered in PDAPP-J20 mice, before vascular morphological changes or blood-brain barrier disruption were evident. At later stages, PDAPP-J20 mice showed decreased hippocampal vascular density and extravasation of fluorescent tracers, indicating vascular and BBB dysfunction. In vitro studies showed that exposure of human brain microvascular endothelial cells (HBMEC) to soluble Aβ40 was sufficient to promote NFκB translocation to the nucleus, leading to a reduction in occludin levels. These changes were prevented by treatment of HBMEC with an inhibitor of the membrane receptor for advanced glycation endproducts (RAGE). Additional results suggest that Aβ42 acts indirectly on the endothelium by inducing astrocytic factors. Furthermore, our results from human and mouse brain samples provide evidence for the crucial involvement of the hippocampal vasculature during Alzheimer's disease.
