Evidence map›Paper›PMID 38747498›Full record

ArticleAnnals of neurology2024

γ-Secretase Modulator BPN15606 Reduced Aβ42 and Aβ40 and Countered Alzheimer-Related Pathologies in a Mouse Model of Down Syndrome.

Xu-Qiao Chen, Ann Becker, Ricardo Albay, Phuong D Nguyen, Dmitry Karachentsev, Amanda J Roberts, Kevin D Rynearson, Rudolph E Tanzi, William C Mobley

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Annals of neurology, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.

0numbers the graph read from it
0cells of the map it votes in
8citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

8 citing papers in PubMed.

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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

9 authors.

Xu-Qiao ChenDepartment of Neurosciences, University of California San Diego, La Jolla, CA, USA.
Ann BeckerDepartment of Neurosciences, University of California San Diego, La Jolla, CA, USA.
Ricardo AlbayDepartment of Neurosciences, University of California San Diego, La Jolla, CA, USA.
Phuong D NguyenDepartment of Neurosciences, University of California San Diego, La Jolla, CA, USA.
Dmitry KarachentsevDepartment of Neurosciences, University of California San Diego, La Jolla, CA, USA.
Amanda J RobertsAnimal Models Core Facility, The Scripps Research Institute, La Jolla, CA, USA.
Kevin D RynearsonDepartment of Neurosciences, University of California San Diego, La Jolla, CA, USA.
Rudolph E TanziGenetics and Aging Research Unit, McCance Center for Brain Health, Department of Neurology, Massachusetts General Hospital, Boston, MA, USA.
William C MobleyDepartment of Neurosciences, University of California San Diego, La Jolla, CA, USA.ORCID 0000-0002-6408-9548

Funding

Multiplexed Single Nucleus RNA and ATAC-seq Sequencing and Cortical Organoids: Transformative Insights into Down SyndromeR01AG070154 · NIA · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI MOBLEY, WILLIAM C, ROSENFELD, MICHAEL G · 2020 to 2020
$5.0M
Antisense Oligonucleotides targeting APP to prevent neurodegeneration in models of Down Syndrome and Alzheimer's diseaseR01AG061151 · NIA · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI MOBLEY, WILLIAM C · 2019 to 2023
$3.4M
Treating with Gamma-Secretase Modulators to Prevent Neurodegeneration in Mouse Models of Down Syndrome and Alzheimer DiseaseR01AG055523 · NIA · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI MOBLEY, WILLIAM C · 2018 to 2022
$3.2M
DH Chen Foundation R-86U55ANational Institutes of Health (NIH) R01AG055523National Institutes of Health (NIH) R01AG061151National Institutes of Health (NIH) R01AG070154NIA NIH HHS R01 AG055523NIA NIH HHS R01 AG061151NIA NIH HHS R01 AG070154the Cure Alzheimer's Fund UCSD 2019-2544
6 · The paper itself

Abstract

objectivesDue to increased gene dose for the amyloid precursor protein (APP), elderly adults with Down syndrome (DS) are at a markedly increased risk of Alzheimer's disease (AD), known as DS-AD. How the increased APP gene dose acts and which APP products are responsible for DS-AD is not well understood, thus limiting strategies to target pathogenesis. As one approach to address this question, we used a novel class of γ-secretase modulators that promote γ-site cleavages by the γ-secretase complex, resulting in lower levels of the Aβ42 and Aβ40 peptides.

methodsTs65Dn mice, which serve as a model of DS, were treated via oral gavage with 10 mg/kg/weekday of BPN15606 (a potent and novel pyridazine-containing γ-secretase modulators). Treatment started at 3 months-of-age and lasted for 4 months.

resultsDemonstrating successful target engagement, treatment with BPN15606 significantly decreased levels of Aβ40 and Aβ42 in the cortex and hippocampus; it had no effect on full-length APP or its C-terminal fragments in either 2 N or Ts65Dn mice. Importantly, the levels of total amyloid-β were not impacted, pointing to BPN15606-mediated enhancement of processivity of γ-secretase. Additionally, BPN15606 rescued hyperactivation of Rab5, a protein responsible for regulating endosome function, and normalized neurotrophin signaling deficits. BPN15606 treatment also normalized the levels of synaptic proteins and tau phosphorylation, while reducing astrocytosis and microgliosis, and countering cognitive deficits.

interpretationOur findings point to the involvement of increased levels of Aβ42 and/or Aβ40 in contributing to several molecular and cognitive traits associated with DS-AD. They speak to increased dosage of the APP gene acting through heightened levels of Aβ42 and/or Aβ40 as supporting pathogenesis. These findings further the interest in the potential use of γ-secretase modulators for treating and possibly preventing AD in individuals with DS. ANN NEUROL 2024;96:390-404.

Indexed as

Alzheimer DiseaseAmyloid beta-PeptidesAmyloid Precursor Protein SecretasesDisease Models, AnimalDown SyndromeMice, TransgenicPeptide FragmentsAmyloid beta-Protein PrecursorAnimalsMaleMiceAmyloid beta-Peptidesamyloid beta-protein (1-40)amyloid beta-protein (1-42)Amyloid beta-Protein PrecursorAmyloid Precursor Protein SecretasesPeptide Fragments

Identifiers

PMID38747498
PMCPMC11236496

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.