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TBK1 interacts with tau and enhances neurodegeneration in tauopathy

ABSTRACT: One of the defining pathological features of Alzheimer’s Disease (AD) is the deposition of neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau in the brain. Aberrant activation of kinases in AD has been suggested to enhance phosphorylation and toxicity of tau, making the responsible tau kinases attractive therapeutic targets. The full complement of tau interacting kinases in AD brain and their activity in disease remains incompletely defined. Here, immunoaffinity enrichment coupled with mass spectrometry (MS) identified TANK-binding kinase 1 (TBK1) as a tau-interacting partner in human AD cortical brain tissues. We validated this interaction in human AD, familial frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) caused by mutations in MAPT (R406W & P301L) and corticobasal degeneration (CBD) postmortem brain tissues as well as human cell lines. Further, we document increased TBK1 activation in both AD and FTDP-17 and map TBK1 phosphorylation sites on tau based on in vitro kinase assays coupled to MS. Lastly, in a Drosophila tauopathy model, activating expression of a conserved TBK1 ortholog triggers tau hyperphosphorylation and enhanced neurodegeneration, whereas knockdown had the reciprocal effect, suppressing tau toxicity. Collectively, our findings suggest that increased TBK1 activation may promote tau hyperphosphorylation and neuronal loss in AD and related tauopathies.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Kidney

DISEASE(S): Frontotemporal Dementia,Alzheimer's Disease

SUBMITTER: Eric Dammer

LAB HEAD: Nicholas T. Seyfried

PROVIDER: PXD025301 | Pride | 2022-03-01

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	MaxQuant-txt.zip	Other
	Uniprot_HUMAN_042015plusApoEisoforms_3constructs.fasta	Fasta
	ma_phospho_01_Tau1.raw	Raw
	ma_phospho_02_Tau2.raw	Raw
	ma_phospho_03_Tau3.raw	Raw

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Project description:Alzheimer’s disease (AD) and vascular dementia (VaD) are the two most common forms of dementia, neither of which can be effectively treated. There is growing evidence on vascular contributions to cognitive impairment and dementia such as AD, but their pathogenic molecular links are not defined yet. Notably, neurofibrillary tangles made of hyperphosphorylated tau (P-tau) are a hallmark lesion of AD, but are not found in VaD. Although brain ischemia induces some tau changes and tau knockout reduces stroke-induced acute brain damage, little is known about the role of tau in mediating progression from vascular insufficiency to later development of VaD. Cis P-tau is a pre-tangle pathology in AD and an early driver of neurodegeneration resulting from brain injury, but its role in AD treatment or in VaD is unknown. Here we identify cis P-tau as an antibody-neutralizable major common early driver of AD and VaD. We show that cis P-tau elimination using cis antibody not only prevents, but also treats AD-like neurodegeneration and memory loss in a hTau mouse model of AD. Purified cis P-tau causes and spreads neurodegeneration with behavioral changes when injected into wild-type mouse brains, but is prevented by cis antibody. Surprisingly, we also find robust cis P-tau with no evidence of tau tangles in human VaD brains and a mouse model of chronic cerebral hypoperfusion that mimics key aspects of clinical VaD. Cis mAb treatment of hypoperfusive mice for 1 or 6 months blocks VaD-like neuropathological and functional outcomes. Single-cell transcriptomic profiling reveals that cerebral hypoperfusion induces numerous global changes in diverse brain cells including those of human AD brains. Remarkably, ~90% of these global changes are fully recovered with cis antibody, correlating with tau expression in cells. Thus, cis P-tau is a major common early driver of AD and VaD, and cis antibody has a potential role in the early detection, prevention and treatment of these devastating diseases.

Project description:The pathophysiology of Alzheimer’s disease (AD) is multifactorial with characteristic extracellular accumulation of amyloid-beta (Aβ) and intraneuronal aggregation of hyperphosphorylated tau in the brain. Development of disease-modifying treatment for AD has been challenging. Recent studies suggest that deleterious alterations in neurovascular cells happens in parallel with Aβ accumulation, inducing tau pathology and necroptosis. Therefore, therapies targeting cellular Aβ and tau pathologies may provide a more effective strategy of disease intervention. Tetramethylpyrazine nitrone (TBN) is a nitrone derivative of tetramethylpyrazine, an active ingredient from Ligusticum wallichii Franchat (Chuanxiong). We previously showed that TBN is a potent scavenger of free radicals with multi-targeted neuroprotective effects in rat and monkey models of ischemic stroke. The present study aimed to investigate the anti-AD properties of TBN. We employed AD-related cellular model (N2a/APPswe) and transgenic mouse model (3×Tg-AD mouse) for mechanistic and behavioral studies. Our results showed that TBN markedly improved cognitive functions and reduced Aβ and hyperphosphorylated tau levels in mouse model. Further investigation of the underlying mechanisms revealed that TBN promoted non amyloidogenic processing pathway of amyloid precursor protein (APP) in N2a/APPswe in vitro. Moreover, TBN preserved synapses from dendritic spine loss and upregulated synaptic protein expressions in 3×Tg-AD mice. Proteomic analysis of 3×Tg-AD mouse hippocampal and cortical tissues showed that TBN induced neuroprotective effects through modulating mitophagy, MAPK and mTOR pathways. In particular, TBN significantly upregulated PINK1, a key protein for mitochondrial homeostasis, implicating PINK1 as a potential therapeutic target for AD. In summary, TBN improved cognitive functions in AD-related mouse model, inhibited Aβ production and tau hyperphosphorylation, and rescued synaptic loss and neuronal damage. Multiple mechanisms underlie the anti-AD effects of TBN including the modulation of APP processing, mTOR signaling and PINK1-related mitophagy.

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TBK1 interacts with tau and enhances neurodegeneration in tauopathy

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