The physiological phosphorylation of tau is critically changed in fetal brains of individuals with Down syndrome

Milenković, Ivan; Jarc, Jasna; Dassler, Eva; Aronica, Eleonora; Iyer, Anand M.; Adle‐Biassette, Homa; Scharrer, Anke; Reischer, Theresa; Hainfellner, Johannes A.; Kovács, Gábor G.

doi:10.1111/nan.12406

Cited by 28 publications

(27 citation statements)

References 56 publications

(72 reference statements)

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“…Similar to the findings described above from the Milenkovic lab (Milenkovic et al, ), in our study we found that levels of phosphorylated Tau residues (p‐(S396) and p‐(T181)‐Tau) were also significantly increased as early as eight years of age in NDEs obtained from blood samples of children with DS (Hamlett, Goetzl, et al, ). The biological mechanisms driving elevated p‐Tau levels early in those with DS remain unknown but recent studies show that exosomes are capable of transferring Tau pathology via seeding in the rodent brain.…”

Section: Exosomal Cargosupporting

confidence: 92%

“…In a neuropathological study of people with DS and of different ages, NFT pathology was observed in 4 cases below 36 years of age and in all 20 cases above that age, again suggesting individual variability in terms of onset (Wegiel, Wisniewski, Dziewiatkowski, Popovitch, & Tarnawski, ). However, although frank NFTs may not appear before the age of 20 in those with DS, a recent report demonstrated abnormal phosphorylation of Tau already in the brain of fetuses with DS, suggesting that alterations in Tau conformation or phosphorylation state is an early event in DS and may contribute to later development of AD pathology (Milenkovic et al, ). Tau phosphorylation at the carboxyl terminus has been shown to be one of the earliest pathological events in DS‐AD (Mondragon‐Rodriguez, Perry, Luna‐Munoz, Acevedo‐Aquino, & Williams, ).…”

Section: Exosomal Cargomentioning

confidence: 99%

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Exosome release and cargo in Down syndrome

Hamlett

LaRosa

Mufson

et al. 2019

Developmental Neurobiology

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Down syndrome (DS) is a multisystem disorder affecting 1 in 800 births worldwide. Advancing technology, medical treatment, and social intervention have dramatically increased life expectancy, yet there are many etiologies of this disorder that are in need of further research. The advent of the ability to capture extracellular vesicles (EVs) in blood from specific cell types allows for the investigation of novel intracellular processes. Exosomes are one type of EVs that have demonstrated great potential in uncovering new biomarkers of neurodegeneration and disease, and also that appear to be intricately involved in the transsynaptic spread of pathogenic factors underlying Alzheimer's disease and other neurological diseases. Exosomes are nanosized vesicles, generated in endosomal multivesicular bodies (MVBs) and secreted by most cells in the body. Since exosomes are important mediators of intercellular communication and genetic exchange, they have emerged as a major research focus and have revealed novel biological sequelae involved in conditions afflicting the DS population. This review summarizes current knowledge on exosome biology in individuals with DS, both early in life and in aging individuals. Collectively these studies have demonstrated that complex multicellular processes underlying DS etiologies may include abnormal formation and secretion of extracellular vesicles such as exosomes.

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Section: Exosomal Cargosupporting

confidence: 92%

Section: Exosomal Cargomentioning

confidence: 99%

Exosome release and cargo in Down syndrome

Hamlett

LaRosa

Mufson

et al. 2019

Developmental Neurobiology

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“…Our data support previous observations about P-Tau in AD-related progression in adults with DS, but also suggest that significant elevations occur, at least in neuron-derived exosomes, at as early as 8 years of age in children with DS. These data have recently been supported by a study from Milenkovic et al (2017) demonstrating changes in Tau phosphorylation even in fetuses with DS, further suggesting that alterations in Tau may contribute to the development of early pathology in the DS brain as early as during fetal development (Milenkovic et al 2017). …”

Section: Introductionmentioning

confidence: 68%

“…Beta amyloid pathology has been detected in post mortem brain samples from people with DS as young as 15 years of age (Lemere et al 1996). Significant changes in Tau protein have been observed in the DS fetal brain (Milenkovic et al 2017), with NFTs observed early in life (Butterfield et al 2014; Perluigi et al 2015; Hartley et al 2015). Despite the fact that AD neuropathology occurs decades prior to the development of dementia in DS-AD, this process has remained relatively unexplored in younger individuals with DS.…”

Section: Introductionmentioning

confidence: 99%

Exosomal biomarkers in Down syndrome and Alzheimer's disease

Hamlett

Ledreux

Potter³

et al. 2018

Free Radical Biology and Medicine

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Every person with Down syndrome (DS) has the characteristic features of Alzheimer’s disease (AD) neuropathology in their brain by the age of forty, and most go on to develop AD dementia. Since people with DS show highly variable levels of baseline function, it is often difficult to identify early signs of dementia in this population. The discovery of blood biomarkers predictive of dementia onset and/or progression in DS is critical for developing effective clinical diagnostics. Our recent studies show that neuron-derived exosomes, which are small extracellular vesicles secreted by most cells in the body, contain elevated levels of amyloid-beta peptides and phosphorylated-Tau that could indicate a preclinical AD phase in people with DS starting in childhood. We also found that the relative levels of these biomarkers were altered following dementia onset. Exosome release and signaling are dependent on cellular redox homeostasis as well as on inflammatory processes, and exosomes may be involved in the immune response, suggesting a dual role as both triggers of inflammation in the brain and propagators of inflammatory signals between brain regions. Based on recently reported connections between inflammatory processes and exosome release, the elevated neuroinflammatory state observed in people with DS may affect exosomal AD biomarkers. Herein, we discuss findings from studies of people with DS, people with DS and AD (DS-AD), and mouse models of DS showing new connections between neuroinflammatory pathways, oxidative stress, exosomes, and exosome-mediated signaling, which may inform future AD diagnostics, preventions, and treatments in the DS population as well as in the general population.

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“…These preliminary observations warrant further examination of Tau binding on a larger cohort, both in fetuses and children with DS to explore potential early Tau alterations in DS. Table 1 Neuropathological staging of AD was con rmed using H & E, silver, amyloid and p-Tau staining 19 , which included Braak and CERAD stages as shown in Table 1 All EOAD cases, with the exception of one, had a Braak stage of V-VI and a CERAD plaque stage of C (de nite AD). LOAD cases were Braak V-VI and a CERAD of C, except for two cases; one had a Braak stage of V-VI and a CERAD of 0-A and a second had Braak stage of VI and a CERAD of B.…”

Section: Quanti Cationmentioning

confidence: 99%

Regional Binding of Tau and Amyloid Pet Tracers in Down Syndrome Autopsy Brain Tissue

Lemoine

Ledreux

Mufson

et al. 2020

Preprint

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INTRODUCTION: Tau pathology is a major age-related event in Down syndrome with Alzheimer’s disease (DS-AD). Although recently, several different Tau PET tracers have been developed as biomarkers for AD, these tracers showed different binding properties in Alzheimer disease and other non-AD tauopathies. They have not been yet investigated in tissue obtained postmortem for DS-AD cases. Here, we evaluated the binding characteristics of two Tau PET tracers (3H-MK6240 and 3H-THK5117) and one amyloid (3H-PiB) ligand in the medial frontal gyrus (MFG) and hippocampus (HIPP) in tissue from adults with DS-AD and DS cases with mild cognitive impairment (MCI) compared to sporadic AD. METHODS: Tau and amyloid autoradiography were performed on paraffin-embedded sections. To confirm respective ligand targets, adjacent sections were immunoreacted for phospho-Tau (AT8) and stained for amyloid staining using Amylo-Glo. RESULTS: The two Tau tracers showed a significant correlation with each other and with AT8, suggesting that both tracers were binding to Tau deposits. 3H-MK6240 Tau binding correlated with AT8 immunostaining but to a lesser degree than the 3H-THK5117 tracer, suggesting differences in binding sites between the two Tau tracers. 3H-THK5117, 3H-MK6240 and 3H-PIB displayed dense laminar binding in the HIPP and MFG in adult DS brains. A regional difference in Tau binding between adult DS and AD was observed suggesting differential regional Tau deposition in adult DS compared to AD, with higher THK binding density in the MFG in adult with DS compared to AD. No significant correlation was found between 3H-PiB and Amylo-Glo staining in adult DS brains suggesting that the amyloid PIB tracer binds to additional sites. CONCLUSIONS: This study provides new insights into the regional binding distribution of a first-generation and a second-generation Tau tracer in limbic and neocortical regions in adults with DS, as well as regional differences in Tau binding in adult with DS vs. those with AD. These findings provide new information about the binding properties of two Tau radiotracers for the detection of Tau pathology in adults with DS in vivo and provide valuable data regarding Tau vs. amyloid binding in adult DS compared to AD.

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The physiological phosphorylation of tau is critically changed in fetal brains of individuals with Down syndrome

Abstract: Our observations suggest functional tau disturbance in DS brains during development, rather than axonal loss. This supports the role of tau as a further important player in the pathophysiology of cognitive impairment in DS and related AD.

Cited by 28 publications

References 56 publications

Exosome release and cargo in Down syndrome

Exosome release and cargo in Down syndrome

Exosomal biomarkers in Down syndrome and Alzheimer's disease

Regional Binding of Tau and Amyloid Pet Tracers in Down Syndrome Autopsy Brain Tissue

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