Dendritic Tau in Alzheimer’s Disease

Ittner, Arne; Ittner, Lars M.

doi:10.1016/j.neuron.2018.06.003

Cited by 206 publications

(216 citation statements)

References 179 publications

(267 reference statements)

Supporting

Mentioning

210

Contrasting

Unclassified

Order By: Relevance

“…This work highlights the potential of AAVs to test several variants of a protein in a time sensitive manner in vivo. Conceptually, this work challenged the long-standing idea of Tau phosphorylation being a purely disease-driven event (Ittner & Ittner, 2018) and suggested that further work is required to examine the physiological and pathological relevance of phosphorylation of Tau protein at individual sites. AAVs offer the opportunity to perform testing of larger number of Tau variants in relevant neuronal culture and in vivo (i.e., disease) models.…”

Section: Post-synaptic Tau Protein In Admentioning

confidence: 95%

Adeno‐associated virus‐based Alzheimer's disease mouse models and potential new therapeutic avenues

Ittner

Klugmann

2019

British J Pharmacology

Self Cite

View full text Add to dashboard Cite

Alzheimer's disease (AD) is a highly prevalent neurodegenerative condition that presents with cognitive decline. The current understanding of underlying disease mechanisms remains incomplete. Genetically modified mouse models have been instrumental in deciphering pathomechanisms in AD. While these models were typically generated by classical transgenesis and genome editing, the use of adeno‐associated viruses (AAVs) to model and investigate AD in mice, as well as to develop novel gene‐therapy approaches, is emerging. Here, we reviewed literature that used AAVs to study and model AD and discuss potential gene therapy strategies. 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

show abstract

Section: Post-synaptic Tau Protein In Admentioning

confidence: 95%

Adeno‐associated virus‐based Alzheimer's disease mouse models and potential new therapeutic avenues

Ittner

Klugmann

2019

British J Pharmacology

Self Cite

View full text Add to dashboard Cite

show abstract

“…Tau is a predominantly cytoplasmic protein that localizes to axons in mature neurons, where it stabilizes the microtubule cytoskeleton. However, Tau mislocalizes to soma and dendrites in tauopathy (Ittner & Ittner, 2018). Furthermore, nuclear or perinuclear localization of Tau has been described (Frost, Hemberg et al, 2014, Maina, Bailey et al, 2018, Sotiropoulos, Galas et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

SETD7-mediated lysine monomethylation is abundant on non-hyperphosphorylated nuclear Tau

Bichmann

Oriol

Ercan-Herbst

et al. 2020

Preprint

View full text Add to dashboard Cite

Human tauopathies including Alzheimer’s disease (AD) are characterized by alterations in the post-translational modification (PTM) pattern of Tau, leading to the formation of insoluble aggregates, neuronal dysfunction and degeneration. Using a mass spectrometry approach, we identified multiple sites of lysine monomethylation on Tau isolated from a detergent-soluble fraction of human brain, some of which were increased in early AD samples. Brain tissues derived from a mouse model of tauopathy demonstrate an age-dependent increase in methylation at specific sites, with methylated Tau enriched in the soluble nuclear fraction and not associated with hyperphosphorylated, insoluble Tau species. Furthermore, we show that the protein lysine methyltransferase SETD7 methylates Tau at K132 and demonstrate an interaction with K130, an additional methylation site in close vicinity. These findings shed light on the function of a novel type of PTM on Tau that provide a potential signal for its translocation to different subcellular sites. Since the mislocalization and depletion of Tau from axons is associated with tauopathies, our findings may furthermore provide insight into this disease-associated phenomenon.

show abstract

“…These dissociated forms of tau can self-assemble into paired-helical filaments (PHFs) gaining further potential to aggregate as Neurofibrillary tangles (NFTs) -a classical neuropathological hallmark of Alzheimer's disease (AD) and related tauopathies 9 . Alternatively, hyperphosphorylated and pathological tau (p-Tau) has been shown to acquire gain-of-toxic function in triggering synaptotoxicity relevant to AD 10 . While AD is the most common form of tauopathy and sixth leading cause of death in the United States 11 , NFT pathology is also the primary etiology in many, but rare tauopathies such as Progressive Supranuclear Palsy (PSP), Pick's disease (PiD), Corticobasal Degeneration (CBD), Fronto-temporal Dementia and Parkinsonism linked to Chromosome-17 tau-type (FTDP-17T) and others 12 .…”

Section: Introductionmentioning

confidence: 99%

Optical induction of autophagy viaTranscription factor EB(TFEB) reduces pathological tau in neurons

Binder

Deretić

Weick

et al. 2019

Preprint

View full text Add to dashboard Cite

Aggregation and accumulation of microtubule associated protein tau in neurons is major neuropathological hallmark of Alzheimer's disease (AD) and related tauopathies. Attempts have been made to promote clearance of pathological tau (p-Tau) from neurons via autophagy. Over expression of transcription factor EB (TFEB), has shown to clear pTau from neurons via autophagy. However, sustained TFEB activation and/or autophagy can create burden on cellular bioenergetics and can be deleterious. Thus, we engineered a minimally invasive optical system that could transiently alter autophagic flux. We optimized and tested an optogenetic gene expression system derived from a previously engineered bacterial transcription factor, EL222. For the first time, our group utilized this system not only to spatial-temporally control nuclear TFEB expression, we also show light-induced TFEB has the capacity to reduce p-Tau burden in AD patient-derived human iPSC-neurons. Together, these results suggest that optically-regulatable gene expression of TFEB unlocks optotherapeutics to treat AD and other dementias.

show abstract

Dendritic Tau in Alzheimer’s Disease

Cited by 206 publications

References 179 publications

Adeno‐associated virus‐based Alzheimer's disease mouse models and potential new therapeutic avenues

Adeno‐associated virus‐based Alzheimer's disease mouse models and potential new therapeutic avenues

SETD7-mediated lysine monomethylation is abundant on non-hyperphosphorylated nuclear Tau

Optical induction of autophagy viaTranscription factor EB(TFEB) reduces pathological tau in neurons

Contact Info

Product

Resources

About