Prevention of tau increase in cerebrospinal fluid of APP transgenic mice suggests downstream effect of BACE1 inhibition

Schelle, Juliane; Häsler, Lisa M.; Göpfert, Jens; Joos, Thomas; Vanderstichele, Hugo; Stoops, Erik; Mandelkow, Eva‐Maria; Neumann, Ulf; Shimshek, Derya R.; Staufenbiel, Matthias; Jucker, Mathias; Kaeser, Stephan A.

doi:10.1016/j.jalz.2016.09.005

Cited by 39 publications

(53 citation statements)

References 23 publications

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“…Cerebrospinal fluid (CSF) was collected from the cisterna magna according to previously published methods (Schelle et al, 2016). Collected blood was incubated for at least 15 min at room temperature and centrifuged at 2,000 g for 10 min, and separated serum was collected and used for sTrem2 measurements.…”

Section: Csf and Serum Collection And Tissue Harvestingmentioning

confidence: 99%

The FTD‐like syndrome causing TREM2 T66M mutation impairs microglia function, brain perfusion, and glucose metabolism

et al. 2017

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Genetic variants in the triggering receptor expressed on myeloid cells 2 (TREM2) increase the risk for several neurodegenerative diseases including Alzheimer's disease and frontotemporal dementia (FTD). Homozygous TREM2 missense mutations, such as p.T66M, lead to the FTD-like syndrome, but how they cause pathology is unknown. Using CRISPR/Cas9 genome editing, we generated a knock-in mouse model for the disease-associated Trem2 p.T66M mutation. Consistent with a loss-of-function mutation, we observe an intracellular accumulation of immature mutant Trem2 and reduced generation of soluble Trem2 similar to patients with the homozygous p.T66M mutation. Trem2 p.T66M knock-in mice show delayed resolution of inflammation upon lipopolysaccharide stimulation and cultured macrophages display significantly reduced phagocytic activity. Immunohistochemistry together with TSPO small animal positron emission tomography (μPET) demonstrates an age-dependent reduction in microglial activity. Surprisingly, perfusion magnetic resonance imaging and FDG-μPET imaging reveal a significant reduction in cerebral blood flow and brain glucose metabolism. Thus, we demonstrate that a TREM2 loss-of-function mutation causes brain-wide metabolic alterations pointing toward a possible function of microglia in regulating brain glucose metabolism.

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Section: Csf and Serum Collection And Tissue Harvestingmentioning

confidence: 99%

The FTD‐like syndrome causing TREM2 T66M mutation impairs microglia function, brain perfusion, and glucose metabolism

et al. 2017

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“…Although these data seem to establish the sequence of events in the development of the human disease, it was not known whether a reduction of Aβ generation by inhibition of BACE‐1 has an effect on tau. Recent studies in old APP23 and middle‐aged APPPS‐1 mice showed elevated CSF tau, and this elevation follows the increased Aβ deposition (Maia et al, ; Schelle et al, ). The elevation of tau in these mice was markedly reduced by treatment with NB‐360 and parallels the treatment effects on deposited Aβ (Schelle et al, ).…”

Section: Effect Of Nb‐360 On Ad‐relevant Pathologies Downstream Of Aβmentioning

confidence: 97%

“…In the vehicle groups, the amount of insoluble Aβ increased 1.5‐fold (3‐month treatment) and approximately fivefold (6‐month treatment). Treatment with NB‐360 significantly reduced the Aβ load compared with the vehicle group for both brain Aβ levels and Aβ immunostaining (Schelle et al, ). The doses applied with the NB‐360‐containing chow were sufficient to keep the Aβ close to the baseline.…”

Section: Effects Of Nb‐360 Treatment On Aβ Pathologymentioning

confidence: 98%

“…The combination of the two mutations enhances the rate of plaque deposition in the double tg mice; both mouse lines show amyloid plaques as early as 1.5–2 months of age. The study in the APPPS‐1 mice was started at 1.5 months of age and continued for 6 months (Schelle et al, ). During this time, the brain Aβ load in the vehicle group increased dramatically (approximately 20‐fold), and almost all of this increase was inhibited in the NB‐360 treatment group, suggesting that the BACE inhibitor could cope even with very high rates of Aβ generation.…”

Section: Effects Of Nb‐360 Treatment On Aβ Pathologymentioning

confidence: 99%

“…Within this time, cortical plaque area and insoluble Aβ load increased about threefold in the vehicle control group, and NB-360 treatment completely prevented this increase and retained the Aβ load at baseline. APP23 mice (with the "Swedish" mutation in the human APP transgene) have been treated with NB-360 starting at 15 months of age for 6.5 months (Schelle et al, 2017) and at 17.5 months of age for 3 months (Beckmann et al, 2016). Compared with the APP51/16 mice at treatment start, APP23 mice have higher amounts of deposited, insoluble Aβ42 in the cortex: 0.14 nmol·g −1 tissue (APP51/16) versus 55 nmol·g −1 tissue in APP23 (15 months), a consequence of the higher Aβ production due to the presence of the "Swedish" mutation (Axelman, Basun, Winblad, & Lannfelt, 1994).…”

Section: Effects Of Nb-360 Treatment On Aβ Pathologymentioning

confidence: 99%

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The β‐secretase (BACE) inhibitor NB‐360 in preclinical models: From amyloid‐β reduction to downstream disease‐relevant effects

Neumann

Machauer

Shimshek

2019

British J Pharmacology

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Inhibition of β‐secretase 1 (BACE‐1; also known as β‐site amyloid precursor protein‐cleaving enzyme‐1) is a current approach to fight the amyloid‐β (Aβ) deposition in the brains of patients with Alzheimer's disease, and a number of BACE‐1 inhibitors are being tested in clinical trials. The BACE‐1 inhibitor NB‐360, although not a clinical compound, turned out to be a valuable pharmacological tool to investigate the effects of BACE‐1 inhibition on the deposition of different Aβ species in amyloid precursor protein (APP) transgenic mice. Furthermore, chronic animal studies with NB‐360 revealed relationships between BACE‐1 inhibition, Aβ deposition, and Aβ‐related downstream effects on neuroinflammation, neuronal function, and markers of neurodegeneration. NB‐360 effects on the processing of physiological BACE‐1 substrates as well as on nonenzymatic BACE‐1 functions have been investigated, complementing studies in BACE‐1 knockout mice. Because NB‐360 is also an inhibitor for BACE‐2, nonclinical studies in adult animals revealed physiological effects of BACE‐2 inhibition. Linked Articles This article is part of a themed section on Therapeutics for Dementia and Alzheimer's Disease: New Directions for Precision Medicine. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.18/issuetoc

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Association of Longitudinal Changes in Cerebrospinal Fluid Total Tau and Phosphorylated Tau 181 and Brain Atrophy With Disease Progression in Patients With Alzheimer Disease

Llibre‐Guerra

Schindler

et al. 2019

JAMA Netw Open

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IMPORTANCE The amyloid/tau/neurodegeneration (A/T/N) framework uses cerebrospinal fluid (CSF) levels of total tau (tTau) as a marker of neurodegeneration and CSF levels of phosphorylated tau 181 (pTau181) as a marker of tau tangles. However, it is unclear whether CSF levels of tTau and pTau181 have similar or different trajectories over the course of Alzheimer disease. OBJECTIVES To examine the rates of change in CSF levels of tTau and pTau181 across the Alzheimer disease course and how the rates of change are associated with brain atrophy as measured by magnetic resonance imaging. DESIGN, SETTING, AND PARTICIPANTS This cohort study was set in tertiary research clinics. Each participant was a member of a pedigree with a known mutation for dominantly inherited Alzheimer disease. Participants were divided into 3 groups on the basis of the presence of a mutation and their Clinical Dementia Rating score. Data analysis was performed in June 2019. MAIN OUTCOMES AND MEASURES Rates of change of CSF tTau and pTau181 levels and their association with the rate of change of brain volume. RESULTS Data from 465 participants (283 mutation carriers and 182 noncarriers) were analyzed. The mean (SD) age of the cohort was 37.8 (11.3) years, and 262 (56.3%) were women. The mean (SD) follow-up duration was 2.7 (1.5) years. Two or more longitudinal CSF and magnetic resonance imaging assessments were available for 160 and 247 participants, respectively. Sixty-five percent of mutation carriers (183) did not have symptoms at baseline (Clinical Dementia Rating score, 0). For mutation carriers, the annual rates of change for CSF tTau and pTau181 became significantly different from 0 approximately 10 years before the estimated year of onset (mean [SE] rates of change, 5.5 [2.8] for tTau [P = .05] and 0.7 [0.3] for pTau 181 [P = .04]) and 15 years before onset (mean [SE] rates of change, 5.4 [3.9] for tTau [P = .17] and 1.1 [0.5] for pTau181 [P = .03]), respectively. The rate of change of pTau181 was positive and increased at the early stages of the disease, showing a positive rate of change starting at 15 estimated years before onset until 5 estimated years before onset (mean [SE], 0.4 [0.3]), followed by a positive but decreasing rate of change at year 0 (mean [SE], 0.1 [0.3]) and then negative rates of change at 5 years (mean [SE], −0.3 [0.4]) and 10 years (mean [SE], −0.6 [0.6]) after symptom onset. In individuals without symptoms (Clinical Dementia Rating score, 0), the rates of change of CSF tTau and pTau181 were negatively associated with brain atrophy (high rates of change in CSF measures were associated with low rates of change in brain volume in asymptomatic stages). After symptom onset (Clinical Dementia Rating score, >0), an increased rate of brain atrophy was not associated with rates of change of levels of both CSF tTau and pTau181. (continued) Key Points Question How do different proposed measurements of tau brain pathologic abnormalities (ie, levels of phosphorylated tau 181 in the cerebrospinal fluid [CSF]) and neurodegenera...

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Prevention of tau increase in cerebrospinal fluid of APP transgenic mice suggests downstream effect of BACE1 inhibition

Cited by 39 publications

References 23 publications

The FTD‐like syndrome causing TREM2 T66M mutation impairs microglia function, brain perfusion, and glucose metabolism

The FTD‐like syndrome causing TREM2 T66M mutation impairs microglia function, brain perfusion, and glucose metabolism

The β‐secretase (BACE) inhibitor NB‐360 in preclinical models: From amyloid‐β reduction to downstream disease‐relevant effects

Association of Longitudinal Changes in Cerebrospinal Fluid Total Tau and Phosphorylated Tau 181 and Brain Atrophy With Disease Progression in Patients With Alzheimer Disease

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