Tau Isoforms Imbalance Impairs the Axonal Transport of the Amyloid Precursor Protein in Human Neurons

Lacovich, Valentina; Espindola, Sonia L.; Alloatti, Matías; Devoto, Victorio Martin Pozo; Cromberg, Lucas Eneas; Čarná, Mária; Forte, Giancarlo; Gallo, Jean‐Marc; Bruno, Luciana; Stokin, Gorazd B.; Avale, María Elena; Falzone, Tomás L.

doi:10.1523/jneurosci.2305-16.2017

Cited by 9 publications

(14 citation statements)

References 6 publications

(37 reference statements)

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“…Tau regulates axon transport polarity by interacting with microtubules and competing for binding of these cargo transport motors [22, 44]. Recently it was reported that the ratio of 3RTau and 4RTau in the axon can alter the direction of transport of APP-containing cargos, with higher levels of 3RTau favoring anterograde transport of APP toward the cell body and inhibiting the retrograde transport of those same cargos [50]. Thus, reducing 3RTau protein could potentially decrease the accumulation of APP and/or Aß in synaptic termini and increase degradation in the cell body.…”

Section: Discussionmentioning

confidence: 99%

Selective targeting of 3 repeat Tau with brain penetrating single chain antibodies for the treatment of neurodegenerative disorders

et al. 2018

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Alzheimer's disease (AD) is the most common form of dementia in the elderly affecting more than 5 million people in the U.S. AD is characterized by the accumulation of β-amyloid (Aβ) and Tau in the brain, and is manifested by severe impairments in memory and cognition. Therefore, removing tau pathology has become one of the main therapeutic goals for the treatment of AD. Tau (tubulin-associated unit) is a major neuronal cytoskeletal protein found in the CNS encoded by the gene MAPT. Alternative splicing generates two major isoforms of tau containing either 3 or 4 repeat (R) segments. These 3R or 4RTau species are differentially expressed in neurodegenerative diseases. Previous studies have been focused on reducing Tau accumulation with antibodies against total Tau, 4RTau or phosphorylated isoforms. Here, we developed a brain penetrating, single chain antibody that specifically recognizes a pathogenic 3RTau. This single chain antibody was modified by the addition of a fragment of the apoB protein to facilitate trafficking into the brain, once in the CNS these antibody fragments reduced the accumulation of 3RTau and related deficits in a transgenic mouse model of tauopathy. NMR studies showed that the single chain antibody recognized an epitope at aa 40-62 of 3RTau. This single chain antibody reduced 3RTau transmission and facilitated the clearance of Tau via the endosomal-lysosomal pathway. Together, these results suggest that targeting 3RTau with highly specific, brain penetrating, single chain antibodies might be of potential value for the treatment of tauopathies such as Pick's Disease.

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Section: Discussionmentioning

confidence: 99%

Selective targeting of 3 repeat Tau with brain penetrating single chain antibodies for the treatment of neurodegenerative disorders

et al. 2018

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“…In addition to recapitulating amyloid and tau changes, iPSCneurons from fAD patients have demonstrated a variety of cellular phenotypes including increased susceptibility to oxidative stress, abnormal endosomes and altered axonal transport (22,26,27). Whether any of these phenotypes can be rescued by modifying the levels or phosphorylation state of tau remains to be determined and will be an important area of future research.…”

Section: Modeling Tau Pathology In Ipsc-neurons From Admentioning

confidence: 99%

“…It is interesting to speculate whether these accelerated neuronal differentiation paradigms will also accelerate the acquisition of mature tau isoforms. The splicing of MAPT can also be artificially controlled to favor 3R or 4R isoform expression using trans-splicing, resulting in altered axonal transport of cargo including APP (27).…”

Section: Tau Splicing In Ipsc-neuronsmentioning

confidence: 99%

Modeling tau pathology in human stem cell derived neurons

Wray¹

2017

Brain Pathology

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Tau pathology is a defining characteristic of multiple neurodegenerative disorders including Alzheimer's disease (AD) and Frontotemporal Dementia (FTD) with tau pathology. There is strong evidence from genetics and experimental models to support a central role for tau dysfunction in neuronal death, suggesting tau is a promising therapeutic target for AD and FTD. However, the development of tau pathology can precede symptom onset by several years, so understanding the earliest molecular events in tauopathy is a priority area of research. Induced pluripotent stem cells (iPSC) derived from patients with genetic causes of tauopathy provide an opportunity to derive limitless numbers of human neurons with physiologically appropriate expression levels of mutated genes for in vitro studies into disease mechanisms. This review discusses the progress made to date using this approach and highlights some of the challenges and unanswered questions this technology has the potential to address.

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“…Therefore, segmental velocities were extracted from tracked APP vesicles registered in kymographs obtained from previous experimental settings. A multimodal distribution of segmental velocities was observed, as previously described 57 , so we propose a Gaussian mixture model with three components to describe each dataset (Materials and Methods). Segmental velocity distribution of moving APP vesicles obtained under harmine treatment showed similar anterograde velocity modes (A, B, C) when compared with DMSO treated neurons (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Since the load of retrograde vesicles into the axon was changed by harmine we ask whether DYRK1A inhibition can also regulate the processive movement of APP in axons. Therefore, we analyzed single particle trajectories of moving APP-YFP vesicles using a modification of previously validated MATLAB routines 56 57 . In-depth analysis of transport dynamics revealed that harmine induce a significant increase in the number of anterograde and retrograde runs only in the net retrograde moving vesicles without impairing the anterograde ones (Fig 1I, J).…”

Section: Resultsmentioning

confidence: 99%

DYRK1A role in microtubule-based axonal transport regulates the retrograde dynamics of APP vesicles in human neurons

Bessone

Karmirian

Goto-Silva

et al. 2021

Preprint

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In Alzheimer ́s Disease (AD) the abnormal intracellular distribution of the amyloid precursor protein (APP) affects its processing and, consequently, the generation of Aβ. Axonal transport plays key roles in the neuronal distribution of APP. The dual-specificity- tyrosine phosphorylation-regulated-kinase-1A (DYRK1A) has been associated with AD onset since its overexpression was found in Down syndrome and sporadic AD patients. Experimental evidence confirmed that APP and tau phosphorylations are mediated by DYRK1A. Moreover, DYRK1A can regulate the cytoskeletal architecture by phosphorylation of both tubulin subunits and microtubule-associated proteins. Therefore, we tested whether DYRK1A has a role in APP axonal transport regulation. We developed highly-polarized human-derived neurons in 2D cultures. At day 14 after terminal plating we inhibited DYRK1A for 48hs with harmine (7.5 μM). DYRK1A overexpression was induced to perform live-cell imaging of APP-loaded vesicles in axons and analyzed transport dynamics. A custom-made MATLAB routine was developed to track and analyze single particle dynamics. Short-term harmine treatment reduced axonal APP vesicles density, due to a reduction in retrograde particles. Contrarily, DYRK1A overexpression enhanced axonal APP density, due to an increase in the retrograde and stationary component. Moreover, both harmine-mediated DYRK1A inhibition and DYRK1A overexpression revealed opposite phenotypes on single particle dynamics, affecting primarily dynein processivity. These results revealed an increased retrieval of distal APP vesicles in axons when DYRK1A is overexpressed and reinforce the suggestion that DYRK1A enhance APP endocytosis. Taken together our results suggest that DYRK1A has a relevant role in the regulation of axonal transport and sub-cellular positioning of APP vesicles. Therefore, our work shed light on the role of DYRK1A in axonal transport regulation, and the putative use of harmine to restore axonal transport impairments.

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Tau Isoforms Imbalance Impairs the Axonal Transport of the Amyloid Precursor Protein in Human Neurons

Cited by 9 publications

References 6 publications

Selective targeting of 3 repeat Tau with brain penetrating single chain antibodies for the treatment of neurodegenerative disorders

Selective targeting of 3 repeat Tau with brain penetrating single chain antibodies for the treatment of neurodegenerative disorders

Modeling tau pathology in human stem cell derived neurons

DYRK1A role in microtubule-based axonal transport regulates the retrograde dynamics of APP vesicles in human neurons

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