Reducing Endogenous Tau Ameliorates Amyloid ß-Induced Deficits in an Alzheimer's Disease Mouse Model

Roberson, Erik D.; Scearce‐Levie, Kimberly; Palop, Jorge J.; Yan, Fengrong; Cheng, Irene H.; Wu, Tiffany; Gerstein, Hilary; Gui, Yu; Mucke, Lennart

doi:10.1126/science.1141736

Cited by 1,709 publications

(1,690 citation statements)

References 30 publications

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“…Possibly related to this effect—and consistent with the observation that reduction of endogenous tau blocks network hyperexcitability and epilepsy of diverse causes 50, 67, 83, 84, 85—both hTau‐WT mice and hTau‐A152T mice were more susceptible to chemically induced epileptiform activity. Similar findings were obtained in hippocampal slice cultures from an independent hTau‐A152T mouse model 74 and in hTau mice carrying the FTDP‐17 mutations G272V, P301L, and R406W 86.…”

Section: Discussionsupporting

confidence: 81%

Expression of A152T human tau causes age‐dependent neuronal dysfunction and loss in transgenic mice

et al. 2016

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A152T‐variant human tau (hTau‐A152T) increases risk for tauopathies, including Alzheimer's disease. Comparing mice with regulatable expression of hTau‐A152T or wild‐type hTau (hTau‐WT), we find age‐dependent neuronal loss, cognitive impairments, and spontaneous nonconvulsive epileptiform activity primarily in hTau‐A152T mice. However, overexpression of either hTau species enhances neuronal responses to electrical stimulation of synaptic inputs and to an epileptogenic chemical. hTau‐A152T mice have higher hTau protein/mRNA ratios in brain, suggesting that A152T increases production or decreases clearance of hTau protein. Despite their functional abnormalities, aging hTau‐A152T mice show no evidence for accumulation of insoluble tau aggregates, suggesting that their dysfunctions are caused by soluble tau. In human amyloid precursor protein (hAPP) transgenic mice, co‐expression of hTau‐A152T enhances risk of early death and epileptic activity, suggesting copathogenic interactions between hTau‐A152T and amyloid‐β peptides or other hAPP metabolites. Thus, the A152T substitution may augment risk for neurodegenerative diseases by increasing hTau protein levels, promoting network hyperexcitability, and synergizing with the adverse effects of other pathogenic factors.

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Section: Discussionsupporting

confidence: 81%

Expression of A152T human tau causes age‐dependent neuronal dysfunction and loss in transgenic mice

et al. 2016

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“…6B and C). Similarly, ablation of the microtubule‐associated protein tau, which has been shown to reduce epileptic activity in a variety of seizure models,28, 30, 31, 32, 33, 34 tended to reduce interictal events by roughly 50% but, if anything, tended to slightly increase the left shift in spectral power in SYN mice (Fig. 6D and E).…”

Section: Resultsmentioning

confidence: 76%

Network dysfunction in α‐synuclein transgenic mice and human Lewy body dementia

Morris

Sanchez

Verret

et al. 2015

Ann Clin Transl Neurol

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ObjectiveDementia with Lewy bodies (DLB) is associated with the accumulation of wild‐type human α‐synuclein (SYN) in neurons and with prominent slowing of brain oscillations on electroencephalography (EEG). However, it remains uncertain whether the EEG abnormalities are actually caused by SYN.MethodsTo determine whether SYN can cause neural network abnormalities, we performed EEG recordings and analyzed the expression of neuronal activity‐dependent gene products in SYN transgenic mice. We also carried out comparative analyses in humans with DLB.ResultsWe demonstrate that neuronal expression of SYN in transgenic mice causes a left shift in spectral power that closely resembles the EEG slowing observed in DLB patients. Surprisingly, SYN mice also had seizures and showed molecular hippocampal alterations indicative of aberrant network excitability, including calbindin depletion in the dentate gyrus. In postmortem brain tissues from DLB patients, we found reduced levels of calbindin mRNA in the dentate gyrus. Furthermore, nearly one quarter of DLB patients showed myoclonus, a clinical sign of aberrant network excitability that was associated with an earlier age of onset of cognitive impairments. In SYN mice, partial suppression of epileptiform activity did not alter their shift in spectral power. Furthermore, epileptiform activity in human amyloid precursor protein transgenic mice was not associated with a left shift in spectral power.InterpretationWe conclude that neuronal accumulation of SYN slows brain oscillations and, in parallel, causes aberrant network excitability that can escalate into seizure activity. The potential role of aberrant network excitability in DLB merits further investigation.

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“…Tau absence confers neuroprotection in several models of neuronal damage, such as traumatic brain injury (Cheng et al , 2014), neuroinflammation (Maphis et al , 2015), amyloid β‐mediated excitotoxicity (Roberson et al , 2007, 2011; Ittner et al , 2010; Vossel et al , 2010), and epilepsy (Holth et al , 2013), among others. Given that acute stress negatively affects AHN (Gould et al , 1992) and considering the neuroprotection exerted by the lack of Tau in the aforementioned models, we addressed whether the Porsolt test would cause similar detrimental effects in Tau −/− and WT mice.…”

Section: Discussionmentioning

confidence: 99%

Novel function of Tau in regulating the effects of external stimuli on adult hippocampal neurogenesis

et al. 2016

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Tau is a microtubule‐associated neuronal protein found mainly in axons. However, its presence in dendrites and dendritic spines is particularly relevant due to its involvement in synaptic plasticity and neurodegeneration. Here, we show that Tau plays a novel in vivo role in the morphological and synaptic maturation of newborn hippocampal granule neurons under basal conditions. Furthermore, we reveal that Tau is involved in the selective cell death of immature granule neurons caused by acute stress. Also, Tau deficiency protects newborn neurons from the stress‐induced dendritic atrophy and loss of postsynaptic densities (PSDs). Strikingly, we also demonstrate that Tau regulates the increase in newborn neuron survival triggered by environmental enrichment (EE). Moreover, newborn granule neurons from Tau−/− mice did not show any stimulatory effect of EE on dendritic development or on PSD generation. Thus, our data demonstrate that Tau−/− mice show impairments in the maturation of newborn granule neurons under basal conditions and that they are insensitive to the modulation of adult hippocampal neurogenesis exerted by both stimulatory and detrimental stimuli.

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Reducing Endogenous Tau Ameliorates Amyloid ß-Induced Deficits in an Alzheimer's Disease Mouse Model

Cited by 1,709 publications

References 30 publications

Expression of A152T human tau causes age‐dependent neuronal dysfunction and loss in transgenic mice

Expression of A152T human tau causes age‐dependent neuronal dysfunction and loss in transgenic mice

Network dysfunction in α‐synuclein transgenic mice and human Lewy body dementia

Novel function of Tau in regulating the effects of external stimuli on adult hippocampal neurogenesis

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