Tau accumulation induces synaptic impairment and memory deficit by calcineurin-mediated inactivation of nuclear CaMKIV/CREB signaling

Abstract

Intracellular accumulation of wild-type tau is a hallmark of sporadic Alzheimer's disease (AD), but the molecular mechanisms underlying tau-induced synapse impairment and memory deficit are poorly understood. Here we found that overexpression of human wild-type full-length tau (termed hTau) induced memory deficits with impairments of synaptic plasticity. Both in vivo and in vitro data demonstrated that hTau accumulation caused remarkable dephosphorylation of cAMP response element binding protein (CREB) in the nuclear fraction. Simultaneously, the calcium-dependent protein phosphatase calcineurin (CaN) was up-regulated, whereas the calcium/ calmodulin-dependent protein kinase IV (CaMKIV) was suppressed. Further studies revealed that CaN activation could dephosphorylate CREB and CaMKIV, and the effect of CaN on CREB dephosphorylation was independent of CaMKIV inhibition. Finally, inhibition of CaN attenuated the hTau-induced CREB dephosphorylation with improved synapse and memory functions. Together, these data indicate that the hTau accumulation impairs synapse and memory by CaN-mediated suppression of nuclear CaMKIV/CREB signaling. Our findings not only reveal new mechanisms underlying the hTau-induced synaptic toxicity, but also provide potential targets for rescuing tauopathies.is the most common neurodegenerative disorder characterized clinically by progressive memory loss (1). The extracellular precipitation of β-amyloid (Aβ) (2), intracellular tau accumulation forming neurofibrillary tangles (3), and profound synapse degeneration are hallmark pathologies in AD brains (4, 5). Studies show that formation of neurofibrillary tangles is positively correlated with the degree of dementia symptoms (6), and the Aβ toxicity needs the presence of tau (7). These data suggest a crucial role of tau accumulation in neurodegeneration and the cognitive impairments in patients with AD. As a cytoskeleton protein, how tau accumulation causes memory deficits is not fully understood.Synapse is the fundamental unit for learning and memory. Dysfunction of synaptic connections is recognized as the cause of memory impairments, and significant synapse loss has been observed in mild cognitive impairment (MCI) and in earlier stages of AD (8). In AD mouse models, synapse impairments appear before the onset of memory deficit (9), whereas amelioration of synapse loss by administration of estradiol preserves cognitive functions (10). Earlier investigations into AD-related synaptic damages have been mainly focused on the toxic effects of Aβ (11). Recently, an emerging role of tau in synaptic impairment has been shown (12). For instance, overexpression of human mutant tau in mice induces synaptic degeneration even in the absence of tangles (13, 14) and reducing endogenous tau in mouse models carrying the mutated amyloid precursor protein (APP) prevents the cognitive deficits and synaptic loss (15).Among many structural or functional proteins involved in synapse development and memory formation, cAMP response element binding protein (CREB) is...

Correcting miR92a-vGAT-Mediated GABAergic Dysfunctions Rescues Human Tau-Induced Anxiety in Mice

“…Coincidently, a remarkable anxiety was reproducibly shown in the mice with CA3 injection of htau in addition to spatial memory deficits. 46 The prefrontal cortex and amygdale have been the recognized brain regions for emotional behaviors; here, we find that hippocampal CA3, a subset with enriched GABAergic neurons, also plays an important role in anxiety behavior. As the htau was expressed in both pyramidal neurons and the GABAergic neurons, it is conceivable that htau accumulation may cause the anxiety behaviors by direct impairment to the GABAergic neurons or indirectly through affecting the synaptic connections between excitatory and the GABAergic neurons.…”

“…By our recent findings, 46,75 we believe that the psychiatric disturbance can reciprocally interact with the onset and/or progression of dementia and vice versa. Another most recent study shows that the relationship between dementia stage and expression of behavioral and psychological symptoms of dementia (BPSD) can be variational according to the type of dementia.…”

CREB overexpression in dorsal CA1 ameliorates long-term memory deficits in aged rats

“…Amyloid –beta treatment reduces CREB levels and can cause it to be retained in the cytoplasm (Arvanitis et al, 2007; Pugazhenthi et al, 2011), while high BACE-1 levels reduce CREB activation (Chen et al, 2012), and CREB-mediated gene expression is aberrant in brains of Alzheimer’s patients (Satoh et al, 2009). A recent study has also shown that Tau accumulation reduces CREB activity by increasing calcineurin levels (Yin et al, 2016). Together, these results suggest that impaired, or sub-optimal CREB function in aging may make aged individuals more vulnerable to Alzheimer’s disease.…”

Tau accumulation triggers STAT 1‐dependent memory deficits by suppressing NMDA receptor expression

“…Intracellular accumulation of tau causes mitochondrial dysfunction and mitophagy deficits by increasing mitochondrial membrane potential [26,27]. Tau accumulation also disrupts intracellular calcium signaling leading to activation of calcineurin and CREB dephosphorylation in primary neuron cultures [4]. These hypothesis-driven studies partially disclose the mechanisms underlying the toxic effects of tau.…”