Cerebrospinal fluid levels of phosphorylated tau and Aβ1-38/Aβ1-40/Aβ1-42 in Alzheimer’s disease with PS1 mutations

Ikeda, Masaki; Yonemura, Keiichi; Kakuda, Satoko; Tashiro, Yuichi; Fujita, Yukio; Takai, Eriko; Hashimoto, Yukiko; Makioka, Kouki; Furuta, Natsumi; Ishiguro, Koichi; Maruki, Risa; Yoshida, Jun‐ichi; Miyaguchi, Osamu; Tsukie, Tamao; Kuwano, Ryouzou; Yamazaki, Tsuneo; Yamaguchi, Hideyo; Amari, Masakuni; Takatama, Masamitsu; Harigaya, Yasuo; Okamoto, Koichi

doi:10.3109/13506129.2013.790810

Cited by 18 publications

(9 citation statements)

References 30 publications

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“…Consistent with this pattern, a previous report of a single asymptomatic ADAD ( APP V717I) MC showed substantial increases in tau and ptau181 over a 4.5 year period very early in the disease process (between 19 and 14 years prior to their EAO) (70), whereas a longitudinal decrease (or a lack of increase) over 5 years in levels of CSF ptau181 have been observed in a small Japanese cohort (n=4) of symptomatic PSEN1 MCs (71). …”

Section: Discussionsupporting

confidence: 79%

Longitudinal Change in CSF Biomarkers in Autosomal-Dominant Alzheimer’s Disease

Fagan

Xiong²,

Jasielec³

et al. 2014

Sci. Transl. Med.

344

279

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Clinicopathologic evidence suggests the pathology of Alzheimer disease (AD) begins many years prior to cognitive symptoms. Biomarkers are required to identify affected individuals during this asymptomatic (“pre-clinical”) stage to permit intervention with potential disease-modifying therapies designed to preserve normal brain function. Studies of families with autosomal-dominant AD (ADAD) mutations provide a unique and powerful means to investigate AD biomarker changes during the asymptomatic period. In this biomarker study comparing cerebrospinal fluid (CSF), plasma and in vivo amyloid imaging, cross-sectional data obtained at baseline in individuals from ADAD families enrolled in the Dominantly Inherited Alzheimer Network (DIAN) demonstrate reduced concentrations of CSF amyloid-β1-42 (Aβ1–42) associated with the presence of β-amyloid plaques, and elevated concentrations of CSF tau, ptau181 and VILIP-1, markers of neurofibrillary tangles and/or neuronal injury/death, in asymptomatic mutation carriers 10-20 years prior to their estimated age at symptom onset (EAO), and prior to detection of cognitive deficits. When compared longitudinally, however, the concentrations of CSF biomarkers of neuronal injury/death within-individuals decrease after their EAO, suggesting a slowing of acute neurodegenerative processes with symptomatic disease progression. These results emphasize the importance of longitudinal, within-person assessment when modeling biomarker trajectories across the course of the disease. If corroborated, this pattern may influence the definition of a positive neurodegenerative biomarker outcome in clinical trials.

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Section: Discussionsupporting

confidence: 79%

Longitudinal Change in CSF Biomarkers in Autosomal-Dominant Alzheimer’s Disease

Fagan

Xiong²,

Jasielec³

et al. 2014

Sci. Transl. Med.

344

279

View full text Add to dashboard Cite

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“…Similar patterns were observed in levels of visinin-like protein 1 (VILIP-1) ( 77 ), a neuronal calcium sensor protein that is a marker of neuronal injury/death ( 78 ). Consistent with this pattern, a previous report of a single asymptomatic ADAD ( APP V717I) MC showed substantial increases in tau and ptau over a 4- to 5-year period very early in the disease process (~EYO −19 to −14) ( 79 ), whereas a longitudinal decrease (or a lack of increase) in ptau was reported in a small Japanese cohort ( n = 4) of symptomatic PSEN1 MCs ( 80 ). Although not often discussed, results consistent with these changes in the trajectories of neuronal injury-related markers have been reported in LOAD ( 81 – 83 ).…”

Section: Csf Biomarkers In Adadsupporting

confidence: 81%

Autosomal Dominant Alzheimer Disease: A Unique Resource to Study CSF Biomarker Changes in Preclinical AD

Schindler

Fagan

2015

Front. Neurol.

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Our understanding of the pathogenesis of Alzheimer disease (AD) has been greatly influenced by investigation of rare families with autosomal dominant mutations that cause early onset AD. Mutations in the genes coding for amyloid precursor protein (APP), presenilin 1 (PSEN-1), and presenilin 2 (PSEN-2) cause over-production of the amyloid-β peptide (Aβ) leading to early deposition of Aβ in the brain, which in turn is hypothesized to initiate a cascade of processes, resulting in neuronal death, cognitive decline, and eventual dementia. Studies of cerebrospinal fluid (CSF) from individuals with the common form of AD, late-onset AD (LOAD), have revealed that low CSF Aβ42 and high CSF tau are associated with AD brain pathology. Herein, we review the literature on CSF biomarkers in autosomal dominant AD (ADAD), which has contributed to a detailed road map of AD pathogenesis, especially during the preclinical period, prior to the appearance of any cognitive symptoms. Current drug trials are also taking advantage of the unique characteristics of ADAD and utilizing CSF biomarkers to accelerate development of effective therapies for AD.

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“…PSEN1 gene mutations contribute to the pathogenesis of early onset AD ( Karch and Goate, 2015 ), and this effect may be mediated by loss of stability and hydrophobicity of the proteins encoded by the mutated variants ( Somavarapu and Kepp, 2016 ). CSF of AD patients with PSEN1 mutations showed lower levels of Aβ than AD patients without PSEN1 mutation ( Ikeda et al, 2013 ). This may suggest that the proteins are retained in the brain cells due to dysregulated autophagy.…”

Section: Biological Mechanisms Linking Autophagy and Admentioning

confidence: 99%

Autophagy and Alzheimer’s Disease: From Molecular Mechanisms to Therapeutic Implications

Uddin

Stachowiak

Mamun

et al. 2018

Front. Aging Neurosci.

319

247

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Alzheimer’s disease (AD) is the most common cause of progressive dementia in the elderly. It is characterized by a progressive and irreversible loss of cognitive abilities and formation of senile plaques, composed mainly of amyloid β (Aβ), and neurofibrillary tangles (NFTs), composed of tau protein, in the hippocampus and cortex of afflicted humans. In brains of AD patients the metabolism of Aβ is dysregulated, which leads to the accumulation and aggregation of Aβ. Metabolism of Aβ and tau proteins is crucially influenced by autophagy. Autophagy is a lysosome-dependent, homeostatic process, in which organelles and proteins are degraded and recycled into energy. Thus, dysfunction of autophagy is suggested to lead to the accretion of noxious proteins in the AD brain. In the present review, we describe the process of autophagy and its importance in AD. Additionally, we discuss mechanisms and genes linking autophagy and AD, i.e., the mTOR pathway, neuroinflammation, endocannabinoid system, ATG7, BCL2, BECN1, CDK5, CLU, CTSD, FOXO1, GFAP, ITPR1, MAPT, PSEN1, SNCA, UBQLN1, and UCHL1. We also present pharmacological agents acting via modulation of autophagy that may show promise in AD therapy. This review updates our knowledge on autophagy mechanisms proposing novel therapeutic targets for the treatment of AD.

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Cerebrospinal fluid levels of phosphorylated tau and Aβ1-38/Aβ1-40/Aβ1-42 in Alzheimer’s disease with PS1 mutations

Cited by 18 publications

References 30 publications

Longitudinal Change in CSF Biomarkers in Autosomal-Dominant Alzheimer’s Disease

Longitudinal Change in CSF Biomarkers in Autosomal-Dominant Alzheimer’s Disease

Autosomal Dominant Alzheimer Disease: A Unique Resource to Study CSF Biomarker Changes in Preclinical AD

Autophagy and Alzheimer’s Disease: From Molecular Mechanisms to Therapeutic Implications

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