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

Vanmechelen, Eugeen; Zetterberg, Henrik; Galgani, Alessandro; Blennow, Kaj; Das, Brati; Yan, Riqiang; Afshar, Mohammad; Aguilar, Lisi Flores; Akman-Anderson, Leyla; Arenas, Joaquín; Ávila, Jesús; Babiloni, Claudio; Baldacci, Filippo; Batrla, Richard; Benda, Norbert; Black, Keith L.; Bokde, Arun L.W.; Bonuccelli, Ubaldo; Broich, Karl; Cacciola, Francesco; Caraci, Filippo; Caruso, Giuseppe; Castrillo, Juan I.; Cavedo, Enrica; Ceravolo, Roberto; Chiesa, Patrizia Andrea; Corbo, Massimo; Corvol, Jean‐Christophe; Cuello, Augusto Claudio; Cummings, Jeffrey L.; Depypere, Herman; Dubois, Bruno; Duggento, Andrea; Emanuele, Enzo; Escott‐Price, Valentina; Federoff, Howard J.; Ferretti, Maria Teresa; Fiandaca, Massimo S.; Frank, Richard A.; Garaci, Francesco; Geerts, Hugo; Giacobini, Ezio; Giorgi, Filippo Sean; Goetzl, Edward J.; Graziani, Manuela; Haberkamp, Marion; Habert, Marie‐Odile; Hänisch, Britta; Hampel, Harald; Herholz, Karl; Hernández, Félix; Imbimbo, Bruno P.; Kapogiannis, Dimitrios; Karran, Eric; Kiddle, Steven; Kim, Seung H.; Koronyo, Yosef; Koronyo-Hamaoui, Maya; Langevin, Todd; Lehericy, Stéphane; Lemercier, Pablo; Lista, Simone; Llavero, Francisco; Lorenceau, Jean; Lucía, Alejandro; Mango, Dalila; Mapstone, Mark; Néri, Christian; Nisticò, Robert; O’Bryant, Sid; Palermo, Giovanni; Perry, George; Ritchie, Craig; Rossi, Símone; Saidi, Amira; Santarnecchi, Emiliano; Schneider, Lon S.; Sporns, Olaf; Toschi, Nicola; Vellas, Bruno; Verdooner, Steven R.; Vergallo, Andrea; Villain, Nicolas; Giudici, Kelly Virecoulon; Watling, Mark; Welikovitch, Lindsay A.; Woodcock, Janet; Younesi, Erfan; Zugaza, José L.

doi:10.1186/s13195-020-00686-3

Cited by 25 publications

(10 citation statements)

References 78 publications

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“…Bace-1 –null mice exhibited phenotypes such as hypomyelination, spontaneous seizures, decreased neurogenesis, and reduced LTP ( 36 ). Expression of these molecules is not detectable in microglia (based on our RNA-seq results), and the effects of these molecules in microglia are minimally affected.…”

Section: Discussionmentioning

confidence: 99%

BACE-1 inhibition facilitates the transition from homeostatic microglia to DAM-1

et al. 2022

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BACE-1 is required for generating β-amyloid (Aβ) peptides in Alzheimer’s disease (AD). Here, we report that microglial BACE-1 regulates the transition of homeostatic to stage 1 disease-associated microglia (DAM-1) signature. BACE-1 deficiency elevated levels of transcription factors including Jun , Jund , Btg2 , Erg1 , Junb , Fos , and Fosb in the transition signature, which transition from more homeostatic to highly phagocytic DAM-1. Consistently, similar transition-state microglia in human AD brains correlated with lowered levels of BACE-1 expression. Targeted deletion of Bace-1 in adult 5xFAD mice microglia elevated these phagocytic microglia, correlated with significant reduction in amyloid plaques without synaptic toxicity. Silencing or pharmacologically inhibiting BACE-1 in cultured microglia-derived cells shows higher phagocytic function in microglia. Mechanistic exploration suggests that abolished cleavage of IL-1R2 and Toll-like receptors via BACE-1 inhibition contributes to the enhanced signaling via the PI3K and p38 MAPK kinase pathway. Together, targeted inhibition of BACE-1 in microglia may offer AD treatment.

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Section: Discussionmentioning

confidence: 99%

BACE-1 inhibition facilitates the transition from homeostatic microglia to DAM-1

et al. 2022

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“…Last, an encouraging observation is the spared side effects associated with synaptic impairments following global deletion or inhibition of BACE-1. BACE-1 cleaves many important neuronal proteins such NRG-1, CHL1, SEZ6, and jagged canonical notch ligand 1 (JAG1), and abolished cleavage of these substrates usually decreases their normal signaling function, as reflected in Bace-1 –null mice, exhibiting phenotypes such as hypomyelination, spontaneous seizures, decreased neurogenesis, and reduced LTP ( 35 ). Expression of these molecules is not detectable in microglia (based on our RNA-seq results), and the effects of these molecules in microglia are minimally affected.…”

Section: Discussionmentioning

confidence: 99%

Targeted BACE-1 inhibition in microglia enhances amyloid clearance and improved cognitive performance

et al. 2022

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Abnormal accumulation of β-amyloid (Aβ) peptides is a culprit in Alzheimer’s disease (AD); blocking Aβ generation is therefore being explored as a logical approach for AD treatment. Here, we demonstrate that targeted inhibition of β-site amyloid precursor protein (APP) cleaving enzyme-1 (BACE-1) in microglia has unique advantages. When Bace-1 was deleted in Alzheimer’s 5xFAD microglia, fewer amyloid plaques developed, and this reduction was not due to changes in APP processing but rather to enhanced Aβ clearance, in line with the increase in a microglial gene signature favoring phagocytosis. Moreover, deletion of Bace-1 in microglia enhances functions of autophagolysosomes and Aβ-induced metabolic reprogramming necessary for Aβ degradation by favoring phosphorylation of mammalian target of rapamycin complex (mTOR) at Ser 2448 and modulating the PI3K–mTOR–HIF-1α signaling pathways. Mice with deletion of Bace-1 in microglia showed no reduction in long-term potentiation, unlike global deletion of Bace-1 . Our results suggest that targeted inhibition of BACE-1 in microglia is a superior strategy for AD treatment.

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“…The assessment of BACE1 parameters (protein concentration, enzymatic activity rates, miRNA, exosomes) in peripheral matrixes, such as plasma, serum, platelets, allows the integration of BACE biomarkers in a non-invasive blood-based liquid biopsy for CNS diseases [ 177 , 178 ].…”

Section: Discussion: Lessons Challenges Pitfalls and Perspectivesmentioning

confidence: 99%

Biological Mechanism-based Neurology and Psychiatry: A BACE1/2 and Downstream Pathway Model

Hampel

Caruso

Nisticò

et al. 2023

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: In Oncology, comprehensive Omics and functional enrichment studies led to an extensive profiling of (epi)genetic and neurobiological alterations that can be mapped onto a single tumor’s clinical phenotype and divergent clinical phenotypes expressing common pathophysiological pathways. Consequently, molecular pathway-based therapeutic interventions for different cancer typologies, namely tumor type- and site-agnostic treatments, have been developed, encouraging real-world implementation of a paradigm shift in medicine. Given the breakthrough nature of the new-generation translational research and drug development in Oncology, there is an increasing rationale to transfertilize this blueprint to other medical fields including Psychiatry and Neurology. To illustrate the emerging paradigm shift in neuroscience, we provide a state-of-the-art review of translational studies on the β-site amyloid precursor protein cleaving enzyme (BACE) and its most studied downstream effector, neuregulin, which are molecular orchestrators of distinct biological pathways involved in several neurological and psychiatric diseases. This body of data aligns with the evidence of a shared genetic/biological architecture among Alzheimer’s disease, schizoaffective and autism spectrum disorders. We engage in a speculative intellectual exercise gravitating around the BACE-related science, here used as paradigmatic case, to facilitating a forward-looking discussion about a potential first step towards the adoption of biological pathway-based, clinical symptom agnostic, categorization models in clinical Neurology and Psychiatry for precision medicine solutions. We draw a perspective whereby pathway-based therapeutic strategies could be catalyzed by high-throughput techniques, embedded in systems-scaled biology, neuroscience, and pharmacology approaches that will help overcome the constraints of traditional descriptive clinical symptom and syndrome-focused constructs in Neurology and Psychiatry.

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

Cited by 25 publications

References 78 publications

BACE-1 inhibition facilitates the transition from homeostatic microglia to DAM-1

BACE-1 inhibition facilitates the transition from homeostatic microglia to DAM-1

Targeted BACE-1 inhibition in microglia enhances amyloid clearance and improved cognitive performance

Biological Mechanism-based Neurology and Psychiatry: A BACE1/2 and Downstream Pathway Model

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