Serum beta-secretase 1 (BACE1) activity as candidate biomarker for late-onset Alzheimer’s disease

Cervellati, Carlo; Trentini, Alessandro; Rosta, Valentina; Passaro, Angelina; Bosi, Cristina; Sanz, Juana María; Bonazzi, Stefania; Pacifico, Salvatore; Seripa, Davide; Valacchi, Giuseppe; Guerini, Remo; Zuliani, Giovanni

doi:10.1007/s11357-019-00127-6

Cited by 40 publications

(47 citation statements)

References 33 publications

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“…BACE1 has been recently found to be increased in the brain/CSF(cerebrospinal fluid) of patients with LOAD or mild cognitive impairment (MCI) 15,16 . BACE1 is present also in serum, as recently demonstrated by our group 17 and Shen et al 18 in two recent studies. In particular, we found that LOAD patients has significantly higher levels of serum BACE1 activity compared to controls, and this difference is independent of possible confounders including age, gender, and other risk factors for dementia 17 .…”

supporting

confidence: 71%

“…BACE1 is present also in serum, as recently demonstrated by our group 17 and Shen et al 18 in two recent studies. In particular, we found that LOAD patients has significantly higher levels of serum BACE1 activity compared to controls, and this difference is independent of possible confounders including age, gender, and other risk factors for dementia 17 . Based on this corollary of evidences, in the present study we investigated whether an increase in serum BACE1 activity is a specific feature of LOAD or might also characterize VAD.…”

supporting

confidence: 71%

“…Our findings further underline the possible shared characteristics between LOAD and VAD, highlighting the potential role of BACE1in the early pathogenesis of these two common types of dementia. Of note, 131 Controls and 115 LOAD were already examined in a previous study 17 .…”

Section: Discussionmentioning

confidence: 99%

“…Briefly, 100 μL of substrate (i.e. H-K(Dabsyl) SEVNLDAEFRC(MAL-LY)-NH 2 which was synthetized as described in 17 ), at a final concentration of 30 μM in the assay, was added to the wells of a black flat-bottom microplate.…”

Section: Bace1 Activity Assaymentioning

confidence: 99%

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Increased blood BACE1 activity as a potential common pathogenic factor of vascular dementia and late onset Alzheimer's disease

Zuliani

Trentini

Rosta

et al. 2020

Sci Rep

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Late onset Alzheimer disease (LOAD) is traditionally considered as a separate disease from vascular dementia (VAD). However, growing evidence suggests that β-amyloid (Aβ) accumulation, that initiates LOAD-related neurodegeneration, is preceded by vascular events. Previous in vitro studies showed that β-secretase 1 (BACE1), the key-enzyme of amyloidogenesis, is upregulated by cerebrovascular insult; moreover, its activity is increased both in brain and serum of LOAD patients. We aimed to investigate whether BACE1 serum activity is altered also in dementias related, or not, to cerebrovascular disease. Thus, we evaluated serum BACE1 activity in a sample of individuals, including patients with LOAD (n. 175), VAD (n. 40), MIXED (LOAD/VAD) dementia (n. 123), other types of dementia (n. 56), and healthy Controls (n. 204). We found that BACE1 was significantly higher not only in LOAD (+ 30%), but also in VAD (+ 35%) and MIXED dementia (+ 22%) (p < 0.001 for all), but not in the other types of dementia (+ 10%). Diagnostic accuracy was 77% for LOAD, 83% for VAD, and 77% for MIXED dementia. In conclusion, we showed for the first time that the increase in peripheral BACE1 activity is a common feature of LOAD and VAD, thus underlying a further pathogenic link between these two forms of dementia.

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supporting

confidence: 71%

supporting

confidence: 71%

Section: Discussionmentioning

confidence: 99%

Section: Bace1 Activity Assaymentioning

confidence: 99%

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Increased blood BACE1 activity as a potential common pathogenic factor of vascular dementia and late onset Alzheimer's disease

Zuliani

Trentini

Rosta

et al. 2020

Sci Rep

Self Cite

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“…Both BACE1 activity and protein concentrations in blood (mostly plasma but in some cases serum) are significantly increased in MCI individuals or patients with ADD compared to HC individuals, with a trend across different disease stages reflecting the direction of expression of the reported CSF biomarkers [34][35][36].…”

Section: Bace1 Biomarkers In Plasmamentioning

confidence: 99%

β-Secretase1 biological markers for Alzheimer’s disease: state-of-art of validation and qualification

Vanmechelen¹,

Zetterberg

Galgani

et al. 2020

Alz Res Therapy

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β-Secretase1 (BACE1) protein concentrations and rates of enzyme activity, analyzed in human bodily fluids, are promising candidate biological markers for guidance in clinical trials investigating BACE1 inhibitors to halt or delay the dysregulation of the amyloid-β pathway in Alzheimer’s disease (AD). A robust body of evidence demonstrates an association between cerebrospinal fluid/blood BACE1 biomarkers and core pathophysiological mechanisms of AD, such as brain protein misfolding and aggregration, neurodegeneration, and synaptic dysfunction. In pharmacological trials, BACE1 candidate biomarkers may be applied to a wide set of contexts of use (CoU), including proof of mechanism, dose-finding, response and toxicity dose estimation. For clinical CoU, BACE1 biomarkers show good performance for prognosis and disease prediction. The roadmap toward validation and qualification of BACE1 biomarkers requires standardized pre-analytical and analytical protocols to reduce inter-site variance that may have contributed to inconsistent results. BACE1 biomarker-drug co-development programs, including biomarker-guided outcomes and endpoints, may support the identification of sub-populations with a higher probability to benefit from BACE1 inhibitors with a reduced risk of adverse effects, in line with the evolving precision medicine paradigm.

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Environmental exposures and the etiopathogenesis of Alzheimer's disease: The potential role of BACE1 as a critical neurotoxic target

Syeda

Cannon

2021

J Biochem & Molecular Tox

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Alzheimer's disease (AD) is a major public health crisis due to devastating cognitive symptoms, a lack of curative treatments, and increasing prevalence. Most cases are sporadic (>95% of cases) after the age of 65 years, implicating an important role of environmental factors in disease pathogenesis. Environmental neurotoxicants have been implicated in neurodegenerative disorders including Parkinson's Disease and AD. Animal models of AD and in vitro studies have shed light on potential neuropathological mechanisms, yet the biochemical and molecular underpinnings of AD‐relevant environmental neurotoxicity remain poorly understood. Beta‐site amyloid precursor protein cleaving enzyme 1 (BACE1) is a potentially critical pathogenic target of environmentally induced neurotoxicity. BACE1 clearly has a critical role in AD pathophysiology: It is required for amyloid beta production and expression and activity of BACE1 are increased in the AD brain. Though the literature on BACE1 in response to environmental insults is limited, current studies, along with extensive AD neurobiology literature suggest that BACE1 deserves attention as an important neurotoxic target. Here, we critically review research on environmental neurotoxicants such as metals, pesticides, herbicides, fungicides, polyfluoroalkyl substances, heterocyclic aromatic amines, advanced glycation end products, and acrolein that modulate BACE1 and potential mechanisms of action. Though more research is needed to clearly understand whether BACE1 is a critical mediator of AD‐relevant neurotoxicity, available reports provide convincing evidence that BACE1 is altered by environmental risk factors associated with AD pathology, implying that BACE1 inhibition and its use as a biomarker should be considered in AD management and research.

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Serum beta-secretase 1 (BACE1) activity as candidate biomarker for late-onset Alzheimer’s disease

Cited by 40 publications

References 33 publications

Increased blood BACE1 activity as a potential common pathogenic factor of vascular dementia and late onset Alzheimer's disease

Increased blood BACE1 activity as a potential common pathogenic factor of vascular dementia and late onset Alzheimer's disease

β-Secretase1 biological markers for Alzheimer’s disease: state-of-art of validation and qualification

Environmental exposures and the etiopathogenesis of Alzheimer's disease: The potential role of BACE1 as a critical neurotoxic target

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