Cerebrospinal fluid neurogranin/β‐site APP‐cleaving enzyme 1 predicts cognitive decline in preclinical Alzheimer's disease

Kirsebom, Bjørn‐Eivind; Nordengen, Kaja; Selnes, Per; Waterloo, Knut; Torsetnes, Silje Bøen; Gísladóttir, Berglind; Brix, Britta; Vanmechelen, Eugeen; Bråthen, Geir; Hessen, Erik; Aarsland, Dag; Fladby, Tormod

doi:10.1016/j.trci.2018.10.003

Cited by 26 publications

(23 citation statements)

References 48 publications

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“…In agreement with De Vos and colleagues, a recent report showed that NGR/BACE1 ratio levels are (i) elevated in both individuals with subjective cognitive decline (SCD) and MCI compared to HC individuals, (ii) associated with smaller hippocampal and amygdala volumes, and (iii) correlate with worse baseline and longitudinal cognitive performance [28].…”

Section: Csf Bace1 and Synaptic Biomarkerssupporting

confidence: 87%

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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Section: Csf Bace1 and Synaptic Biomarkerssupporting

confidence: 87%

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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“…In AD, neuropathology builds up for years before the development of MCI. Prior CSF biomarker studies suggest that levels of neurogranin, a ratio of NPTX2 to another synaptic peptide, ratios between other synaptic peptides (e.g., neurogranin/BACE1), or CSF levels of a panel of synaptic proteins may correlate with cognitive changes before the advent of clinically recognizable MCI [11,16,45]. Our results support this emerging concept by showing relationships between synaptic biomarkers in CSF and cognition in cognitively normal elders, but further research is clearly warranted.…”

Section: Discussionmentioning

confidence: 99%

Synaptic biomarkers in CSF aid in diagnosis, correlate with cognition and predict progression in MCI and Alzheimer's disease

Galasko

Xiao

et al. 2019

A&D Transl Res & Clin Interv

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129

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Introduction Amyloid, Tau, and neurodegeneration biomarkers can stage Alzheimer's Disease (AD). Synaptic biomarkers may help track cognition. Methods In cognitively normal controls, Mild Cognitive Impairment (MCI) and AD, we investigated CSF biomarkers in relation to cognitive measures and as predictors of cognitive and global decline. Results There were 90 normal controls (mean age 73.0, 58% women), 57 MCI (mean age 74.3, 35% women), and 46 AD (mean age 70.7, 41% women). CSF Aβ1‐42 and Neuronal Pentraxin 2 (NPTX2) were decreased, and CSF Tau, neurogranin, and SNAP25 increased in AD versus controls. Aβ1‐42/Tau or NPTX2/Tau discriminated AD and controls best. NPTX2/Tau correlated strongly with cognition in AD and MCI and predicted a 2–3‐year decline. We replicated findings in the ADNI cohort. Discussion CSF synaptic biomarkers, particularly NPTX2, which regulates synaptic homeostasis, relate to cognition and predict progression in AD beyond Aβ1‐42 and Tau. This is relevant for prognosis and clinical trials.

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“…We detect them as early as the 'Mild AD' stage, but nd much more of them at 'Moderate' and 'Severe' AD stages. Thus, the Aβ-GAPDH complexes may serve as a reliable biomarker of AD progression, comparable to other already established markers like CSF amyloid beta 42 (Aβ42), total tau (t-tau), and tau phosphorylated at threonine 181 (p-tau) [43], or recently proposed ones like neurogranin/β-site APP-cleaving enzyme 1 (Ng/BACE1) [44].…”

Section: Discussionmentioning

confidence: 77%

Extracellular GAPDH promotes Alzheimer disease progression by enhancing amyloid-β aggregation and cytotoxicity

Lazarev

Tsolaki

Mikhaylova

et al. 2020

Preprint

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Background Neuronal cell death during Alzheimer disease (AD) causes the release of cytosolic proteins, particularly glyceraldehyde-3-phosphate dehydrogenase (GAPDH), which forms highly cytotoxic detergent-insoluble complexes with amyloid-β (Aβ) and promotes neurodegeneration. Methods We detected and quantified the complex formation between Aβ and GAPDH released from brain tissue of patients with AD using ultrafiltration, and fluorescence resonance energy transfer (FRET). To explore the biochemical and structural features of Aβ-GAPDH complexes we employed novel immunoenzyme assays and atomic force microscopy. Lentiviral infection in situ was used to elevate GAPDH in brain tissue of rat and mouse models of AD. The Morris maize water test, MRI, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), and lactate dehydrogenase (LDH)-activity assays were used to characterize the effects of Aβ-GAPDH complexes in animal and cellular models of AD. Results Here we report that GAPDH forms stable aggregates with extracellular Aβ. We detected these aggregates in cerebrospinal fluid (CSF) from AD patients at levels directly proportional to the progressive stages of AD. We found that GAPDH forms a covalent bond with Q15 of Aβ that is mediated by transglutaminase (tTG). The Q15A substitution weakens the interaction between Aβ and GAPDH and reduces Aβ-GAPDH cytotoxicity. Lentivirus-driven GAPDH overexpression in two AD animal models increased the level of apoptosis of hippocampal neurons, neuronal degeneration, and cognitive dysfunction. In contrast, in vivo knockdown of GAPDH reversed these pathogenic abnormalities suggesting a pivotal role of GAPDH in Aβ-stimulated neurodegeneration. CSF obtained from animals with enhanced GAPDH expression demonstrated increased cytotoxicity in vitro . Furthermore, RX-624, a specific GAPDH small molecular ligand reduced accumulation of Aβ aggregates and reversed memory deficit in AD transgenic mice. Conclusions Extracellular GAPDH compromises Aβ clearance and accelerates neurodegeneration, thus representing a promising pharmacological target for AD.

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Cerebrospinal fluid neurogranin/β‐site APP‐cleaving enzyme 1 predicts cognitive decline in preclinical Alzheimer's disease

Cited by 26 publications

References 48 publications

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

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

Synaptic biomarkers in CSF aid in diagnosis, correlate with cognition and predict progression in MCI and Alzheimer's disease

Extracellular GAPDH promotes Alzheimer disease progression by enhancing amyloid-β aggregation and cytotoxicity

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