Tau Reduction Prevents Key Features of Autism in Mouse Models

Tai, Cheng‐Chi; Chang, Chieh; Yu, Gui-Qiu; López, Isabel Álvarez; Yu, Xinxing; Wang, Xin; Guo, Weikun; Mucke, Lennart

doi:10.1016/j.neuron.2020.01.038

Cited by 69 publications

(117 citation statements)

References 89 publications

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“…In support of this notion, Tau has been shown to interact with other phosphatases, such as protein phosphatase 2A, through its proline-rich domain, which is also recognized by Fyn [51]. During the revision of our manuscript, a study has been published which shows that Tau indeed interacts with PTEN via Tau's proline-rich domain [57]. As diseaserelevant phosphorylation or FTLD mutations of Tau can increase the association with Fyn [3,31], these pathological changes may release PTEN from being restricted by Tau.…”

Section: Discussionmentioning

confidence: 58%

PTEN activation contributes to neuronal and synaptic engulfment by microglia in tauopathy

et al. 2020

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Phosphatase and tensin homolog (PTEN) regulates synaptic density in development; however, whether PTEN also regulates synapse loss in a neurodegenerative disorder such as frontotemporal lobar degeneration with Tau deposition (FTLD-Tau) has not been explored. Here, we found that pathological Tau promotes early activation of PTEN, which precedes apoptotic caspase-3 cleavage in the rTg4510 mouse model of FTLD-Tau. We further demonstrate increased synaptic and neuronal exposure of the apoptotic signal phosphatidylserine that tags neuronal structures for microglial uptake, thereby linking PTEN activation to synaptic and neuronal structure elimination. By applying pharmacological inhibition of PTEN's protein phosphatase activity, we observed that microglial uptake can be decreased in Tau transgenic mice. Finally, we reveal a dichotomous relationship between PTEN activation and age in FTLD-Tau patients and healthy controls. Together, our findings suggest that in tauopathy, PTEN has a role in the synaptotoxicity of pathological Tau and promotes microglial removal of affected neuronal structures.

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Section: Discussionmentioning

confidence: 58%

PTEN activation contributes to neuronal and synaptic engulfment by microglia in tauopathy

et al. 2020

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“…In contrast, in a mouse line of Shank3B -/-(SH3 and multiple ankyrin repeat domains 3 deficiency, modeling the Phelan McDermid Syndrome), Tau reduction was not beneficial. The authors suggested that the PI3K/Akt/mTOR (protease inhibitor 13/ AKT Serine/Threonine kinase/mTOR) pathway, activated by interactions of Tau and PTEN (phosphatase and tensin homolog) plays a key role in the ASD development in the Scn1a RX/+ and the Cntnap2 -/cases, but not in the Shank3B -/mouse 37 . Notably, MTOR was found to be regulated by ADNP in human postmortem tissues (Fig.…”

Section: Discussionmentioning

confidence: 99%

Tauopathy in the young autistic brain: novel biomarker and therapeutic target

et al. 2020

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Given our recent discovery of somatic mutations in autism spectrum disorder (ASD)/intellectual disability (ID) genes in postmortem aged Alzheimer's disease brains correlating with increasing tauopathy, it is important to decipher if tauopathy is underlying brain imaging results of atrophy in ASD/ID children. We concentrated on activity-dependent neuroprotective protein (ADNP), a prevalent autism gene. The unique availability of multiple postmortem brain sections of a 7-year-old male, heterozygous for ADNP de novo mutation c.2244Adup/p.His559Glnfs*3 allowed exploration of tauopathy, reflecting on a general unexplored mechanism. The tested subject exhibited autism, fine motor delays, severe intellectual disability and seizures. The patient died after multiple organ failure following liver transplantation. To compare to other ADNP syndrome mutations, immortalized lymphoblastoid cell lines from three different patients (including ADNP p.Arg216*, p.Lys408Valfs*31, and p.Tyr719* heterozygous dominant mutations) and a control were subjected to RNA-seq. Immunohistochemistry, high-throughput gene expression profiles in numerous postmortem tissues followed. Comparisons to a control brain and to extensive datasets were used. Live cell imaging investigated Tau-microtubule interaction, protecting against tauopathy. Extensive child brain tauopathy paralleled by multiple gene expression changes was discovered. Tauopathy was explained by direct mutation effects on Tau-microtubule interaction and correction by the ADNP active snippet NAP. Significant pathway changes (empirical P value < 0.05) included over 100 genes encompassing neuroactive ligand-receptor and cytokine-cytokine receptor interaction, MAPK and calcium signaling, axon guidance and Wnt signaling pathways. Changes were also seen in steroid biosynthesis genes, suggesting sex differences. Selecting the most affected genes by the ADNP mutations for gene expression analysis, in multiple postmortem tissues, identified Tau (MAPT)-gene-related expression changes compared with extensive normal gene expression (RNA-seq) databases. ADNP showed relatively reduced expression in the ADNP syndrome cerebellum, which was also observed for 25 additional genes (representing >50% of the tested genes), including NLGN1, NLGN2, PAX6, SMARCA4, and SNAP25, converging on nervous system development and tauopathy. NAP provided protection against mutated ADNP disrupted Tau-microtubule association. In conclusion, tauopathy may explain brain-imaging findings in ADNP syndrome children and may provide a new direction for the development of tauopathy protecting drug candidates like NAP in ASD/ID.

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“…Tau appears to be important for permitting seizure activity, and there is strong evidence that MAPT −/− mice [148], or mice treated with tau antisense oligonucleotides [59] are resistant to pentylenetetrazol-induced seizures. Crossing MAPT −/− mice with genetic models of epilepsy [105], AD [219] and ASD [249] can rescue hyperexcitability and spontaneous epileptiform activity. As such, a role for tau in promoting or regulating neuronal excitability seems likely.…”

Section: Regulating Neuronal Hyperexcitability: Could Tau and Aβ Act mentioning

confidence: 99%

The physiological roles of tau and Aβ: implications for Alzheimer’s disease pathology and therapeutics

2020

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Tau and amyloid beta (Aβ) are the prime suspects for driving pathology in Alzheimer’s disease (AD) and, as such, have become the focus of therapeutic development. Recent research, however, shows that these proteins have been highly conserved throughout evolution and may have crucial, physiological roles. Such functions may be lost during AD progression or be unintentionally disrupted by tau- or Aβ-targeting therapies. Tau has been revealed to be more than a simple stabiliser of microtubules, reported to play a role in a range of biological processes including myelination, glucose metabolism, axonal transport, microtubule dynamics, iron homeostasis, neurogenesis, motor function, learning and memory, neuronal excitability, and DNA protection. Aβ is similarly multifunctional, and is proposed to regulate learning and memory, angiogenesis, neurogenesis, repair leaks in the blood–brain barrier, promote recovery from injury, and act as an antimicrobial peptide and tumour suppressor. This review will discuss potential physiological roles of tau and Aβ, highlighting how changes to these functions may contribute to pathology, as well as the implications for therapeutic development. We propose that a balanced consideration of both the physiological and pathological roles of tau and Aβ will be essential for the design of safe and effective therapeutics.

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Tau Reduction Prevents Key Features of Autism in Mouse Models

Cited by 69 publications

References 89 publications

PTEN activation contributes to neuronal and synaptic engulfment by microglia in tauopathy

PTEN activation contributes to neuronal and synaptic engulfment by microglia in tauopathy

Tauopathy in the young autistic brain: novel biomarker and therapeutic target

The physiological roles of tau and Aβ: implications for Alzheimer’s disease pathology and therapeutics

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