Role of monomeric amyloid-β in cognitive performance in Alzheimer's disease: Insights from clinical trials with secretase inhibitors and monoclonal antibodies

Imbimbo, Bruno P.; Ippati, Stefania; Watling, Mark; Imbimbo, Camillo

doi:10.1016/j.phrs.2022.106631

Cited by 34 publications

(13 citation statements)

References 83 publications

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“…Secretases such as BACE1 are known to be elevated in the brains of AD patients, making them an attractive therapeutic target 16,27 . Elevated expression of GM1, GM2, or GD2 increases β- and γ-site cleavages of APP 28 .…”

Section: Discussionmentioning

confidence: 99%

Apolipoprotein-based regulation of ganglioside metabolism upon secretase activity inhibition in iPSC-derived cerebral organoids

Jha,

Váňová,

Bohačiaková

et al. 2023

Preprint

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Beta and gamma-secretase inhibitors have been of pharmacological interest to reduce abeta (Aβ) formation and aggregation, a defining characteristic of Alzheimer's disease (AD). Recent research indicates that Apolipoprotein E (ApoE), another genetic risk factor for AD, can regulate secretase activity. Secretase inhibitor-induced elevation of neuronal membrane lipids has been documented in 2D models. Due to their enhanced ability to reproduce AD-like pathology and ease of performing the experimental intervention, we utilized a 3D model comprised of pluripotent stem cells generated from AD patients. We treated patient-derived ApoE3 and ApoE4 cerebral organoids with beta and gamma-secretase inhibitors to determine if organoids could reproduce the differences observed in the 2D model and if the alteration in secretase activity could affect the regulation of neuronal lipids synthesis in an ApoE-dependent manner. Ganglioside profiling was accomplished using liquid chromatography/electrospray ionization tandem mass spectrometry (LC/ESI-MS/MS) via selective reaction monitoring (SRM). The inhibitor administration elevated the levels of ganglioside and ceramide in ApoE4-derived organoids. Since gangliosides are known to enhance Aβ fibrillogenesis, our study implies that reduction in secretase activity affects neuronal membrane architecture that could eventually aggravate AD, particularly in patients with the ApoE4 isoform. In addition, the ability of organoids to replicate results from other experimental models demonstrates their potential to improve translatability significantly.

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Section: Discussionmentioning

confidence: 99%

Apolipoprotein-based regulation of ganglioside metabolism upon secretase activity inhibition in iPSC-derived cerebral organoids

Jha,

Váňová,

Bohačiaková

et al. 2023

Preprint

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“…The brain of mice with DM showed hyperphosphorylation of tau levels and accumulation of β-amyloid (Aβ) plaque (Oliveira et al, 2021 ). Aβ is a product of amyloid precursor protein (APP) and is degraded or cleared by an insulin-degrading enzyme (IDE) (Lee et al, 2017 ; Díaz et al, 2022 ; Imbimbo et al, 2023 ). Tau primarily provides stabilization to microtubules in the part of axons and dendrites and shows a loss of microtubule binding for the hyperphosphorylation in AD.…”

Section: Introductionmentioning

confidence: 99%

Natural bioactive compounds in Alzheimer's disease: From the perspective of type 3 diabetes mellitus

Huang

Mao

et al. 2023

Front. Aging Neurosci.

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There is a close relationship between Alzheimer's disease (AD) and diabetes mellitus (DM), and the link between the two is often referred to as type 3 diabetes mellitus (T3DM). Many natural bioactive compounds have shown the potential to treat AD and diabetes. We mainly review the polyphenols represented by resveratrol (RES) and proanthocyanidins (PCs) and alkaloids represented by berberine (BBR) and Dendrobium nobile Lindl. alkaloids (DNLA) from the perspective of T3DM to review the neuroprotective effects and molecular mechanisms of natural compounds in AD.

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“…While some cite concerns regarding publications bias and other design issues (11), others cite lack of clinical relevance of the reported effect size (12). Common counter arguments include that newer monoclonal antibody drugs targeting protofibrils instead of other amyloid species may confer benefits that earlier drug classes did not, as they can achieve greater reductions in the relevant species that is not necessarily captured by simple measure of overall change in amyloid (13)(14)(15) or because of nonlinear effects such that the cognitive benefits can only be achieved with the amyloid reductions produced by these newer medications (16).…”

Section: Introductionmentioning

confidence: 99%

Estimated Effects of Amyloid Reduction on Cognitive Change: A Bayesian Update across a Range of Priors

Ackley

Wang

Chen

et al. 2023

Preprint

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Introduction: Results of the CLARITY-AD and GRADUATE I and II trials rekindled discussion on the impact of amyloid-targeting drugs. We use a Bayesian approach to quantify how a rational observer might update their prior beliefs based on new trial results. Methods: We used publicly available data from the CLARITY-AD and GRADUATE I & II trials to estimate the effect of reducing amyloid on CDR-SB score. A range of prior positions were then updated according to Bayes Theorem using these estimates. Results: After updating with new trial data, a wide range of starting positions resulted in credible intervals that did not include no effect of amyloid reduction on CDR-SB. Discussion: For a range of starting beliefs and assuming veracity of underlying data, rational observers would conclude there is a small benefit of amyloid-reductions due to amyloid targeting drugs on cognition. This benefit must be weighed against opportunity cost and side effect risk.

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Role of monomeric amyloid-β in cognitive performance in Alzheimer's disease: Insights from clinical trials with secretase inhibitors and monoclonal antibodies

Cited by 34 publications

References 83 publications

Apolipoprotein-based regulation of ganglioside metabolism upon secretase activity inhibition in iPSC-derived cerebral organoids

Apolipoprotein-based regulation of ganglioside metabolism upon secretase activity inhibition in iPSC-derived cerebral organoids

Natural bioactive compounds in Alzheimer's disease: From the perspective of type 3 diabetes mellitus

Estimated Effects of Amyloid Reduction on Cognitive Change: A Bayesian Update across a Range of Priors

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