Early elevation of BACE1 in dementia

Cervellati, Carlo; Valacchi, Giuseppe; Zuliani, Giovanni

doi:10.18632/aging.203727

Cited by 2 publications

(3 citation statements)

References 7 publications

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“…A Spearman test suggests an overall trend for the correlation (ρ = 0.3575, p = 0.0795) between relative BACE1 values and absolute Aβ34 levels. Notably, in agreement with this data, serum BACE1 activity was found to be ~ 30% higher in AD patients compared to controls 30,31 . In addition, Aβ40 and Aβ42 species were significantly elevated in the AD group by ~ 44and ~ 23-fold, respectively (Fig.…”

Section: Resultssupporting

confidence: 89%

Mechanisms of amyloid-β34 generation indicate a pivotal role for BACE1 in amyloid homeostasis

Ulku

Liebsch

Åkerman

et al. 2023

Sci Rep

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The beta‑site amyloid precursor protein (APP) cleaving enzyme (BACE1) was discovered due to its “amyloidogenic” activity which contributes to the production of amyloid-beta (Aβ) peptides. However, BACE1 also possesses an “amyloidolytic” activity, whereby it degrades longer Aβ peptides into a non‑toxic Aβ34 intermediate. Here, we examine conditions that shift the equilibrium between BACE1 amyloidogenic and amyloidolytic activities by altering BACE1/APP ratios. In Alzheimer disease brain tissue, we found an association between elevated levels of BACE1 and Aβ34. In mice, the deletion of one BACE1 gene copy reduced BACE1 amyloidolytic activity by ~ 50%. In cells, a stepwise increase of BACE1 but not APP expression promoted amyloidolytic cleavage resulting in dose-dependently increased Aβ34 levels. At the cellular level, a mislocalization of surplus BACE1 caused a reduction in Aβ34 levels. To align the role of γ-secretase in this pathway, we silenced Presenilin (PS) expression and identified PS2-γ-secretase as the main γ-secretase that generates Aβ40 and Aβ42 peptides serving as substrates for BACE1’s amyloidolytic cleavage to generate Aβ34.

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Section: Resultssupporting

confidence: 89%

Mechanisms of amyloid-β34 generation indicate a pivotal role for BACE1 in amyloid homeostasis

Ulku

Liebsch

Åkerman

et al. 2023

Sci Rep

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“…Aβ is one of the most characteristic pathologic hallmarks of AD and plasma A β was found to be positively associated with CSF A β , thus applying plasma A β as a prescreener in the cohort recruitment would reduce the number of lumbar punctures by 51% 8 . As initiator of A β generation, 7 BACE1 plasma concentration was found to be 53.2% and 68.9% higher in MCI and AD participants compared to that of cognitively normal (CN) individuals 9 . Recent papers demonstrated strong evidence that plasma p‐tau181 may be used to predict subsequent progression to AD dementia in MCI subjects, 10 as well as CN individuals 11 .…”

Section: Introductionmentioning

confidence: 99%

“…8 As initiator of Aβ generation, 7 BACE1 plasma concentration was found to be 53.2% and 68.9% higher in MCI and AD participants compared to that of cognitively normal (CN) individuals. 9 Recent papers demonstrated strong evidence that plasma p-tau181 may be used to predict subsequent progression to AD dementia in MCI subjects, 10 as well as CN individuals. 11 Similarly, by using cox regression model, the longitudinal serum NfL level was found could be used to track neurodegeneration throughout the preclinical and different clinical stages of AD.…”

Section: Introductionmentioning

confidence: 99%

Blood biomarkers in dynamic prediction of conversion to Alzheimer's disease: An application of joint modeling

Yuan,

Lian,

et al. 2024

Int J Geriat Psychiatry

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ObjectivesTo investigate the accuracy of longitudinal trajectories of blood biomarkers for predicting future onset of AD among MCI participants as well as to demonstrate dynamic prediction of the individual conversion risk applying joint modeling.MethodsA total of 446 participants with MCI at baseline from the Alzheimer's Disease Neuroimaging Initiative database were included. We introduced joint modeling to analyze the effects of the longitudinal blood biomarkers on the conversion risk to AD, and further to build individual‐specific prediction risk model.ResultsDuring the follow‐up, 345 participants remained with MCI and 101 progressed to AD, and were categorized as non‐progression and progression group, respectively. Longitudinally, the positive association of the concentration dynamics of plasma p‐tau181 and NfL with the conversion risk to AD from MCI was also demonstrated, with Hazard Ratio (HR) = 5.83 and HR = 4.18, respectively. When incorporating plasma p‐tau181 and NfL together to predict AD progression, we observed improved performance (AUC = 0.701, Brier Score = 0.119). Two participants were chosen to exemplify the individual‐specific risk prediction at different follow‐up time for comparative analysis.ConclusionsPlasma p‐tau181 and NfL could serve as biomarkers for the prediction of AD onset, and the individualized prediction opens up the possibility to provide clinical information at a personal level.

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Early elevation of BACE1 in dementia

Cited by 2 publications

References 7 publications

Mechanisms of amyloid-β34 generation indicate a pivotal role for BACE1 in amyloid homeostasis

Mechanisms of amyloid-β34 generation indicate a pivotal role for BACE1 in amyloid homeostasis

Blood biomarkers in dynamic prediction of conversion to Alzheimer's disease: An application of joint modeling

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