Peripheral complement interactions with amyloid β peptide in Alzheimer's disease: 2. Relationship to amyloid β immunotherapy

Crane, Andrés; Brubaker, William D.; Johansson, Jenny U.; Trigunaite, Abhishek; Ceballos, Justine; Bradt, Bonnie M.; Glavis-Bloom, Courtney; Wallace, Tanya L.; Tenner, Andrea J.; Rogers, Joseph

doi:10.1016/j.jalz.2017.04.015

Cited by 28 publications

(39 citation statements)

References 40 publications

(60 reference statements)

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“…However, the results from testing therapeutic mAbs were mystifying, since some have failed and showed a lack of efficacy and have many side effects. Others have boosted the experience in improving and developing better candidates, beside others that showed enhanced Aβ clearance . According to many reports, the stage of initiating the intervention in clinical trials is very critical, since targeting Aβ in early stages of AD or prophylactically may exhibit better impact than in late stages of AD .…”

Section: Alternative Interventions To Prevent Aβ Accumulation By Immumentioning

confidence: 99%

“…Others have boosted the experience in improving and developing better candidates, 112 beside others that showed enhanced Aβ clearance. 117 According to many reports, the stage of initiating the intervention in clinical trials is very critical, since targeting Aβ in early stages of AD or prophylactically may exhibit better impact than in late stages of AD. 118 Table 5, summarizes many of these engineered antibodies including bapineuzumab, solanezumab, ponezumab, gantenerumab, aducanumab, and crenezumab.…”

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confidence: 99%

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BACE1 inhibitors: Current status and future directions in treating Alzheimer's disease

Moussa-Pacha

Abdin

Omar

et al. 2019

Medicinal Research Reviews

212

175

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Alzheimer's disease (AD) is an irreversible, progressive neurodegenerative brain disorder with no current cure. One of the important therapeutic approaches of AD is the inhibition of β‐site APP cleaving enzyme‐1 (BACE1), which is involved in the rate‐limiting step of the cleavage process of the amyloid precursor protein (APP) leading to the generation of the neurotoxic amyloid β (Aβ) protein after the γ‐secretase completes its function. The produced insoluble Aβ aggregates lead to plaques deposition and neurodegeneration. BACE1 is, therefore, one of the attractive targets for the treatment of AD. This approach led to the development of potent BACE1 inhibitors, many of which were advanced to late stages in clinical trials. Nonetheless, the high failure rate of lead drug candidates targeting BACE1 brought to the forefront the need for finding new targets to uncover the mystery behind AD. In this review, we aim to discuss the most promising classes of BACE1 inhibitors with a description and analysis of their pharmacodynamic and pharmacokinetic parameters, with more focus on the lead drug candidates that reached late stages of clinical trials, such as MK8931, AZD‐3293, JNJ‐54861911, E2609, and CNP520. In addition, the manuscript discusses the safety concerns and insignificant physiological effects, which were highlighted for the most successful BACE1 inhibitors. Furthermore, the review demonstrates with increasing evidence that despite tremendous efforts and promising results conceived with BACE1 inhibitors, the latest studies suggest that their clinical use for treating Alzheimer's disease should be reconsidered. Finally, the review sheds light on alternative therapeutic options for targeting AD.

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Section: Alternative Interventions To Prevent Aβ Accumulation By Immumentioning

confidence: 99%

mentioning

confidence: 99%

BACE1 inhibitors: Current status and future directions in treating Alzheimer's disease

Moussa-Pacha

Abdin

Omar

et al. 2019

Medicinal Research Reviews

212

175

View full text Add to dashboard Cite

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“…The mechanism should be enhanced by beta-amyloid antibodies that form immune complexes (ICs) with Aβ and therefore may be relevant to current beta-amyloid immunotherapy approaches. Targeting peripheral mechanisms that may facilitate beta-amyloid clearance has the potential as immunotherapy to treat Alzheimer’s disease [ 24 ].…”

Section: Omplement S Ystem In mentioning

confidence: 99%

Synaptic Pruning in Alzheimer’s Disease: Role of the Complement System

Brucato¹,

Benjamin²

2020

GJMR

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“…CR1 is also camouflaged by itself (26.5% dark CDS), where the repeated region includes the extracellular C3b and C4b binding domain. The number of repeats and density of certain isoforms have been associated with Alzheimer’s disease [21, 42-45]. (e) HLA-DRB5 is dark by depth in the ADSP and gnomAD data (50.2% dark CDS).…”

Section: Resultsmentioning

confidence: 99%

Systematic analysis of dark and camouflaged genes: disease-relevant genes hiding in plain sight

Ebbert

Jensen

Jansen-West

et al. 2019

Preprint

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Background The human genome contains ‘dark’ gene regions that cannot be adequately assembled or aligned using standard short-read sequencing technologies, preventing researchers from identifying mutations within these gene regions that may be relevant to human disease. Here, we identify regions that are ‘dark by depth’ (few mappable reads) and others that are ‘camouflaged’ (ambiguous alignment), and we assess how well long-read technologies resolve these regions. We further present an algorithm to resolve most camouflaged regions (including in short-read data) and apply it to the Alzheimer’s Disease Sequencing Project (ADSP; 13142 samples), as a proof of principle. Results Based on standard whole-genome lllumina sequencing data, we identified 37873 dark regions in 5857 gene bodies (3635 protein-coding) from pathways important to human health, development, and reproduction. Of the 5857 gene bodies, 494 (8.4%) were 100% dark (142 protein-coding) and 2046 (34.9%) were ≥5% dark (628 protein-coding). Exactly 2757 dark regions were in protein-coding exons (CDS) across 744 genes. Long-read sequencing technologies from 10x Genomics, PacBio, and Oxford Nanopore Technologies reduced dark CDS regions to approximately 45.1%, 33.3%, and 18.2% respectively. Applying our algorithm to the ADSP, we rescued 4622 exonic variants from 501 camouflaged genes, including a rare, ten-nucleotide frameshift deletion in CR1, a top Alzheimer’s disease gene, found in only five ADSP cases and zero controls. Conclusions While we could not formally assess the CR1 frameshift mutation in Alzheimer’s disease (insufficient sample-size), we believe it merits investigating in a larger cohort. There remain thousands of potentially important genomic regions overlooked by short-read sequencing that are largely resolved by long-read technologies.

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Peripheral complement interactions with amyloid β peptide in Alzheimer's disease: 2. Relationship to amyloid β immunotherapy

Abstract: Together with our previous results, showing significant Alzheimer's disease deficits in peripheral Aβ clearance, the present findings strongly suggest that peripheral mechanisms should not be ignored as contributors to the effects of Aβ immunotherapy.

Cited by 28 publications

References 40 publications

BACE1 inhibitors: Current status and future directions in treating Alzheimer's disease

BACE1 inhibitors: Current status and future directions in treating Alzheimer's disease

Synaptic Pruning in Alzheimer’s Disease: Role of the Complement System

Systematic analysis of dark and camouflaged genes: disease-relevant genes hiding in plain sight

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