Tau Phosphorylation In Hippocampus Research Articles

Beneficial effects of caffeine in a transgenic model of Alzheimer's disease-like tau pathology

Tau pathology found in Alzheimer's disease (AD) is crucial in cognitive decline. Epidemiologic evidences support that habitual caffeine intake prevents memory decline during aging and reduces the risk to develop Alzheimer's disease. So far, experimental studies addressed the impact of caffeine in models mimicking the amyloid pathology of AD. However, in vivo effects of caffeine in a model of AD-like tauopathy remain unknown. Here, we evaluated effects of chronic caffeine intake (0.3 g/L through drinking water), given at an early pathologic stage, in the THY-Tau22 transgenic mouse model of progressive AD-like tau pathology. We found that chronic caffeine intake prevents from the development of spatial memory deficits in tau mice. Improved memory was associated with reduced hippocampal tau phosphorylation and proteolytic fragments. Moreover, caffeine treatment mitigated several proinflammatory and oxidative stress markers found upregulated in the hippocampus of THY-Tau22 animals. Together, our data support that moderate caffeine intake is beneficial in a model of AD-like tau pathology, paving the way for future clinical evaluation in AD patients.

ß-amyloid induces a dying-back process and remote trans-synaptic alterations in a microfluidic-based reconstructed neuronal network

Recent histopathological studies have shown that neurodegenerative processes in Alzheimer's and Parkinson's Disease develop along neuronal networks and that hallmarks could propagate trans-synaptically through neuronal pathways. The underlying molecular mechanisms are still unknown, and investigations have been impeded by the complexity of brain connectivity and the need for experimental models allowing a fine manipulation of the local microenvironment at the subcellular level. In this study, we have grown primary cortical mouse neurons in microfluidic (μFD) devices to separate soma from axonal projections in fluidically isolated microenvironments, and applied β-amyloid (Aβ) peptides locally to the different cellular compartments. We observed that Aβ application to the somato-dendritic compartment triggers a “dying-back” process, involving caspase and NAD+ signalling pathways, whereas exposure of the axonal/distal compartment to Aβ deposits did not induce axonal degeneration. In contrast, co-treatment with somatic sub-toxic glutamate and axonal Aβ peptide triggered axonal degeneration. To study the consequences of such subcellular/local Aβ stress at the network level we developed new μFD multi-chamber devices containing funnel-shaped micro-channels which force unidirectional axon growth and used them to recreate in vitro an oriented cortico-hippocampal pathway. Aβ application to the cortical somato-dendritic chamber leads to a rapid cortical pre-synaptic loss. This happens concomitantly with a post-synaptic hippocampal tau-phosphorylation which could be prevented by the NMDA-receptor antagonist, MK-801, before any sign of axonal and somato-dendritic cortical alteration. Thanks to μFD-based reconstructed neuronal networks we evaluated the distant effects of local Aβ stress on neuronal subcompartments and networks. Our data indicates that distant neurotransmission modifications actively take part in the early steps of the abnormal mechanisms leading to pathology progression independently of local Aβ production. This offers new tools to decipher mechanisms underlying Braak's staging. Our data suggests that local Aβ can play a role in remote tauopathy by distant disturbance of neurotransmission, providing a putative mechanism underlying the spatiotemporal appearance of pretangles.

Effect of Chronic Noise Exposure on Expression of N-Methyl-D-Aspartic Acid Receptor 2B and Tau Phosphorylation in Hippocampus of Rats

ObjectiveTo study the effect of chronic noise exposure on expression of N-methyl-D-aspartic acid receptor 2B (NR2B) and tau phosphorylation in hippocampus of rats. MethodsTwenty-four male SD rats were divided in control group and chronic noise exposure group. NR2B expression and tau phosphorylation in hippocampus of rats were detected after chronic noise exposure (100 dB SPL white noise, 4 h/d×30d) and their mechanisms underlying neuronal apoptosis in hippocampus of rats with TUNEL staining. ResultsThe NR2B expression decreased significantly after chronic noise exposure which resulted in tau hyperphosphorylation and neural apoptosis in hippocampus of rats. Immunohistochemistry showed that the tau hyperphosphorylation was most prominent in dentate gyrus (DG) and CA1 region of rat hippocampus. ConclusionThe abnormality of neurotransmitter system, especially Glu and NR2B containing NMDA receptor, and tau hyperphosphorylation in hippocampus of rats, may play a role in chronic noise-induced neural apoptosis and cognition impairment.

Deferoxamine inhibits iron induced hippocampal tau phosphorylation in the Alzheimer transgenic mouse brain

Prior work has shown that iron interacts with hyperphosphorylated tau, which contributes to the formation of neurofibrillary tangles (NFTs) in Alzheimer’s disease (AD), whereas iron chelator desferrioxamine (DFO) slows down the clinical progression of the cognitive decline associated with this disease. However, the effects of DFO on tau phosphorylation in the presence or absence of iron have yet to be determined. Using amyloid precursor protein (APP) and presenilin 1 (PS1) double transgenic mouse brain as a model system, we investigated the effects and potential mechanisms of intranasal administration of DFO on iron induced abnormal tau phosphorylation. High-dose iron treatment markedly increased the levels of tau phosphorylation at the sites of Thr205, Thr231 and Ser396, whereas highly induced tau phosphorylation was abolished by intranasal administration of DFO in APP/PS1 transgenic mice. Moreover, DFO intranasal administration also decreases Fe-induced the activities of cyclin-dependent kinase 5 (CDK5) and glycogen synthase kinase 3β (GSK3β), which in turn suppressing tau phosphorylation. Cumulatively, our data show that intranasal DFO treatment exerts its suppressive effects on iron induced tau phosphorylation via CDK5 and GSK3β pathways. More importantly, elucidation of DFO mechanism in suppressing tau phosphorylation may provide insights for developing therapeutic strategies to combat AD.

Clusterin regulates β-amyloid toxicity via Dickkopf-1-driven induction of the wnt–PCP–JNK pathway

Although the mechanism of Aβ action in the pathogenesis of Alzheimer's disease (AD) has remained elusive, it is known to increase the expression of the antagonist of canonical wnt signalling, Dickkopf-1 (Dkk1), whereas the silencing of Dkk1 blocks Aβ neurotoxicity. We asked if clusterin, known to be regulated by wnt, is part of an Aβ/Dkk1 neurotoxic pathway. Knockdown of clusterin in primary neurons reduced Aβ toxicity and DKK1 upregulation and, conversely, Aβ increased intracellular clusterin and decreased clusterin protein secretion, resulting in the p53-dependent induction of DKK1. To further elucidate how the clusterin-dependent induction of Dkk1 by Aβ mediates neurotoxicity, we measured the effects of Aβ and Dkk1 protein on whole-genome expression in primary neurons, finding a common pathway suggestive of activation of wnt–planar cell polarity (PCP)–c-Jun N-terminal kinase (JNK) signalling leading to the induction of genes including EGR1 (early growth response-1), NAB2 (Ngfi-A-binding protein-2) and KLF10 (Krüppel-like factor-10) that, when individually silenced, protected against Aβ neurotoxicity and/or tau phosphorylation. Neuronal overexpression of Dkk1 in transgenic mice mimicked this Aβ-induced pathway and resulted in age-dependent increases in tau phosphorylation in hippocampus and cognitive impairment. Furthermore, we show that this Dkk1/wnt–PCP–JNK pathway is active in an Aβ-based mouse model of AD and in AD brain, but not in a tau-based mouse model or in frontotemporal dementia brain. Thus, we have identified a pathway whereby Aβ induces a clusterin/p53/Dkk1/wnt–PCP–JNK pathway, which drives the upregulation of several genes that mediate the development of AD-like neuropathologies, thereby providing new mechanistic insights into the action of Aβ in neurodegenerative diseases.

Role of stereotaxically injected IgG from db/db mice in the phosphorylation of the microtubule-associated protein tau in hippocampus

People with type 2 diabetes (T2DM) mellitus are high risk for dementia and Alzheimer's disease (AD) via several plausible pathways. However, the underlying mechanisms have been still unclear, and the relation of immune injury to the pathogenesis of T2DM-related AD is not yet completely understood. Our present study aimed to elucidate the possible role of immunoglobulin IgG in the immune process of AD associated with T2DM in db/db mice. Hippocampi of 20 db/db mice and 20 C57BL/6 mice were subjected to immunohistochemistry and immunofluorescence assays. The phosphorylation of tau, glycogen synthase kinase (GSK)-3β and AKT activity was examined by Western blot analysis. IgG purified from the sera of IgG deposit-positive db/db mice was stereotaxically injected into the hippocampi of another 12 db/db mice and 12 C57BL/6 mice. The phosphorylation of tau, Abeta, GSK-3β and AKT activity was analyzed. Compared with the C57BL/6 control, 13 of the 20 db/db mice exhibited high levels of IgG deposits in the hippocampus. Treatment with IgG triggered tau hyperphosphorylations and Abeta deposition, which are likely major factors in AD. Meanwhile, IgG inhibited AKT phosphorylation and promoted GSK-3β activity. The IgG deposits observed in some db/db mice were possibly related to the impairment of T2DM-related AD development. Some autoimmune processes may be involved in AD in type 2 diabetes mellitus development at the level of the hippocampus.

Tau Phosphorylation and Sevoflurane Anesthesia

BACKGROUND There is a growing interest in the involvement of anesthetic agents in the etiology of postoperative cognitive dysfunction. Recent animal studies suggest that acute anesthesia induces transient hyperphosphorylation of tau, an effect essentially ascribed to hypothermia. The main aim of the present study was to investigate effects, in normothermic conditions, of acute or repeated exposure to sevoflurane, a halogenated anesthetic agent, on hippocampal tau phosphorylation and spatial memory in adult mice. METHODS 5 to 6-month-old C57Bl6/J mice were submitted to acute (1 h) or repeated (five exposures of 1h every month) anesthesia using 1.5 or 2.5% sevoflurane, in normothermic conditions. In the acute protocol, animals were sacrificed 1 and 24 h after exposure. In the chronic protocol, spatial memory was evaluated using the Morris water maze following the fourth exposure, and tau phosphorylation evaluated 1 month following the last exposure using bi- and mono-dimensional electrophoresis. RESULTS Acute sevoflurane anesthesia in normothermic conditions led to a significant dose-dependent and reversible hippocampal tau phosphorylation, 1 h following the end of exposure (P < 0.001). Conversely, repeated anesthesia led to persistent tau hyperphosphorylation and significant memory impairments, as seen in the retention phase of the Morris water maze in sevoflurane-anesthesized animals. These pathologic features may be related to the activation of both Akt and Erk pathways. CONCLUSIONS The present study demonstrates, in mice, that sevoflurane exposure is associated with increased tau phosphorylation through specific kinases activation and spatial memory deficits. These data support a correlation between exposures to this anesthetic agent and cognitive decline.

Tau Phosphorylation and Sevoflurane Anesthesia

There is a growing interest in the involvement of anesthetic agents in the etiology of postoperative cognitive dysfunction. Recent animal studies suggest that acute anesthesia induces transient hyperphosphorylation of tau, an effect essentially ascribed to hypothermia. The main aim of the present study was to investigate effects, in normothermic conditions, of acute or repeated exposure to sevoflurane, a halogenated anesthetic agent, on hippocampal tau phosphorylation and spatial memory in adult mice. 5 to 6-month-old C57Bl6/J mice were submitted to acute (1 h) or repeated (five exposures of 1h every month) anesthesia using 1.5 or 2.5% sevoflurane, in normothermic conditions. In the acute protocol, animals were sacrificed 1 and 24 h after exposure. In the chronic protocol, spatial memory was evaluated using the Morris water maze following the fourth exposure, and tau phosphorylation evaluated 1 month following the last exposure using bi- and mono-dimensional electrophoresis. Acute sevoflurane anesthesia in normothermic conditions led to a significant dose-dependent and reversible hippocampal tau phosphorylation, 1 h following the end of exposure (P < 0.001). Conversely, repeated anesthesia led to persistent tau hyperphosphorylation and significant memory impairments, as seen in the retention phase of the Morris water maze in sevoflurane-anesthesized animals. These pathologic features may be related to the activation of both Akt and Erk pathways. The present study demonstrates, in mice, that sevoflurane exposure is associated with increased tau phosphorylation through specific kinases activation and spatial memory deficits. These data support a correlation between exposures to this anesthetic agent and cognitive decline.

A novel glycogen synthase kinase‐3 inhibitor 2‐methyl‐5‐(3‐{4‐[(S )‐methylsulfinyl]phenyl}‐1‐benzofuran‐5‐yl)‐1,3,4‐oxadiazole decreases tau phosphorylation and ameliorates cognitive deficits in a transgenic model of Alzheimer’s disease

Alzheimer's disease (AD) is a neurodegenerative disorder leading to a progressive loss of cognitive function and is pathologically characterized by senile plaques and neurofibrillary tangles. Glycogen synthase kinase-3 (GSK-3) is involved in AD pathogenesis. GSK-3 is reported not only to phosphorylate tau, a major component of neurofibrillary tangles, but also to regulate the production of amyloid β, which is deposited in senile plaques. Therefore, pharmacological inhibition of GSK-3 is considered an attractive therapeutic approach. In this study, we report the pharmacological effects of a novel GSK-3 inhibitor, 2-methyl-5-(3-{4-[(S)-methylsulfinyl]phenyl}-1-benzofuran-5-yl)-1,3,4-oxadiazole (MMBO), which displays high selectivity for GSK-3 and brain penetration following oral administration. MMBO inhibited tau phosphorylation in primary neural cell culture and also in normal mouse brain. When administered to a transgenic mouse model of AD, MMBO significantly decreased hippocampal tau phosphorylation at GSK-3 sites. Additionally, chronic MMBO administration suppressed tau pathology as assessed by AT8-immunoreactivity without affecting amyloid β pathology. Finally, in behavioral assessments, MMBO significantly improved memory and cognitive deficits in the Y-maze and in novel object recognition tests in the transgenic AD mouse model. These results indicate that pharmacological GSK-3 inhibition ameliorates behavioral dysfunction with suppression of tau phosphorylation in an AD mouse model, and that MMBO might be beneficial for AD treatment.

Impulse noise exposure in rats causes cognitive deficits and changes in hippocampal neurotransmitter signaling and tau phosphorylation

Noise exposure has been characterized as a stressor, and its non-auditory effects on the central nervous system have been established both epidemiologically and experimentally. Little is known about the impact of impulse noise on the brain, however. In this study, we examined the effects of impulse noise stress on spatial learning and memory and on associated changes in the hippocampus. Rats were exposed to 20 sound impulses with a peak sound pressure of 165 dB and duration of 100 ms. Impulse noise stress led to a temporary decrease in cognitive function as evidenced by poor spatial memory in the Morris water maze (MWM). Effects of noise on the glutamate (Glu)–N-methyl- d-aspartic acid receptor (NMDAR) signaling system and hippocampal tau phosphorylation were investigated by high performance liquid chromatography, Western blotting, and immunohistochemistry. The concentrations of Glu and aspirate (Asp) in the hippocampus were increased at 30 min after exposure and remained elevated for the entire observation period (24 h), while the content of glycine (Gly) was stable for several hours following noise but also increased by 24 h after noise stress. Impulse noise stress also caused a significant increase in NMDAR 2B subunit (NR2B) expression and a two-phase increase in tau phosphorylation in hippocampus. Immunohistochemistry confirmed tau hyperphosphorylation in hippocampus that was most prominent in the dentate gyrus (DG) and CA1 region. These findings demonstrate that impulse noise stress impairs early spatial memory, possibly by disrupting Glu-NMDAR signaling and triggering aberrant tau hyperphosphorylation in hippocampus.

Cerebral ischemia aggravates cognitive impairment in a rat model of Alzheimer's disease

AimAutopsy evidence suggests that the presence of both Alzheimer's disease (AD) and cerebral infarction pathology is associated with more severe cognitive impairment than that produced by AD pathology alone. This study aims to investigate the effect of cerebral ischemia on cognitive function in rats with AD constructed by hippocampal injection and to determine its underlying mechanism, which is proposed to be of significance to the treatment of AD. Main methodsAD was modeled by injection of aggregated Aβ(1–40), either alone or followed by hippocampal endothelin-1 injection to mimic cerebral ischemia in hippocampus, into the right dentate gyrus (DG) of rats. The Morris water maze was used to evaluate cognitive function. Aβ deposition, neuronal loss and phosphorylated tau expression in hippocampus were examined by Congo red staining, Nissl's staining and immunohistochemistry, respectively. Reactive astrocytes, IL-1β and TNF-α expressions were measured by immunohistochemistry, in situ hybridization and reverse transcription–polymerase chain reaction. Key findingsCompared with rats treated with either Aβ or endothelin alone, rats treated with both Aβ and endothelin showed more aggravated cognitive impairment and more Aβ deposits, neuron loss, phosphorylated tau expression, reactive astrocytes, IL-1β and TNF-α expressions in hippocampus. SignificanceHippocampal ischemia aggravates cognitive impairment of AD rats by increasing Aβ deposits, neuron loss and tau phosphorylation in hippocampus. The enhanced inflammatory response may be responsible for cerebral ischemia-induced aggravation of cognitive impairment in AD rats. Based on these findings, prevention and treatment of cerebral ischemia may improve clinical symptoms of AD and suppress the progression of AD.

Increased hippocampal tau phosphorylation and axonal mitochondrial transport in a mouse model of chronic stress

Corticotropin-releasing hormone (CRH) is considered the driving force of the hypothalamo-pituitary-adrenal (HPA) axis and plays an important role in mood regulation. The HPA axis is reported to be closely related to acute stress-induced tau phosphorylation in the rodent hippocampus. However, the relationship between the hyperactive HPA axis and tau phosphorylation in the hippocampus and hence the functional implications for chronic stress are not fully understood. In this study, we aimed to examine tau phosphorylation and the effect on axonal transport of mitochondria in the hippocampus of a chronic stress model. A mouse model was created by neonatal isolation before weaning, followed by chronic mild stress by social isolation after weaning. Behavioural tests showed that the model had a typical depression/anxiety-like behaviour accompanied by increased plasma corticosterone level and hypothalamic CRH mRNA expression. Phosphorylated tau increased significantly, accompanied by increased synaptosomal mitochondrial levels in hippocampus of the chronic stress model. CRH receptor 1 antagonist (CP154,526) treatment, not glucocorticoid receptor antagonist (RU486) treatment, decreased tau phosphorylation and synaptosomal mitochondrial levels in the hippocampus of the mouse model. Consistent with an in-vivo model, when hyperphosphorylated tau was inhibited by lithium in cultured primary hippocampal neurons, mitochondrial transport monitored by live imaging was also decreased. We show here for the first time that phosphorylated tau in the hippocampus of a chronic stress model, accompanied by increased mitochondrial transport, was mediated by CRH receptor 1, not by glucocorticoid receptors, which suggests that centrally derived CRH may be involved in the process of mitochondrial axon transport and hence play an important role in hippocampus of a chronic stress model.

Tau phosphorylation in hippocampus results in toxic gain-of-function

The MAP (microtubule-associated protein) tau binds to tubulin, the main component of MTs (microtubules), which results in the stabilization of MT polymers. Tau binds to the C-terminal of tubulin, like other MAPs (including motor proteins such as kinesin) and it therefore may compete with these proteins for the same binding site in the tubulin molecule. In pathological conditions, tau is the main component of aberrant protein aggregates found in neurodegenerative disorders known as tauopathies where tau is present in its hyperphosphorylated form. GSK3 (glycogen synthase kinase 3, also known as tau kinase I) has been described as one of the main kinases involved in tau modifications. We have analysed the role of phospho-tau as a neurotoxic agent. We have analysed a transgenic mouse model which overexpresses GSK3beta. In this transgenic mouse, a clear degeneration of the dentate gyrus, which increases with age, was found. In a double transgenic mouse, which overexpresses GSK3 and tau at the same time, dentate gyrus degeneration was dramatically increased. This result may suggest that phospho-tau may be toxic inside neurons of the dentate gyrus. Once neuronal degeneration takes place, intracellular tau is secreted to the extracellular space. The present review discusses the toxicity of this extracellular tau for surrounding neurons.

Ischemia/reperfusion induces hippocampal tau hyperphosphorylation in rats via ER stress

The main clinical symptoms of Alzhermer's Disease (AD) patients are cognitive impairment and the degraded learning and memory ability. The amount of intracellular neurofibrillary (NFTs) formed by hyperphosphorylated tau is closely positivecorrelated with the clinical dementia degree of AD patients. Phosphorylation of tau is mainly regulated by protein kinase glycogen synthase kinase-3 (GSK-3β) and phosphatase protein phosphatase 2A (PP2A). Brain Ischemia/reperfusion is a frequent important pathophysiological process of brain injury. Some scholars have proposed “ischemia / reperfusion” hypothesis of AD and regard the reischemia/reperfusion as an important pathophysiological pathogenesis in the sporadic AD. Ischemia/reperfusion can cause cell stress response, such as endoplasmic reticulum stress (ER Stress). GRP78/Bip as an inherent molecular chaperone in the endoplasmic reticulum is the marker of ER stress. The increased ER stress and expression of Bip were found in the AD brain. To investigate that whether ischemia or ischemia/reperfusion can affect tau phosphorylation via the ER stress. The SD rats were used to make the animal models of cerebral ischemia 20min and ischemia/reperfusion (1d, 3d, 5d) by bilateral carotid artery occlusion and the inhibitor of ER stress, 4-phenyl butyric acid (PBA) was used. The phosphorylation levels of tau protein, the expressions and activities of GSK-3β, PP2A catalytic subunit (PP2Ac) were observed. The results showed that reperfusion after ischemia 20min induced significantly increased tau phosphorylation in hippocampus at the Ser396, Ser404, Ser198/199/202 sites and increased Bip expression after ischemia 20min and reperfusion (1d, 3d, 5d). The expressions of GSK-3β and PP2Ac had no significant change after ischemia and ischemia/reperfusion. The increased phosphorylation levels of GSK-3β at Tyr216 after ischemia and reperfusion and decreased phosphorylation levels at Ser9 after reperfused 3d and 5d, and increased phosphorylation levels at Tyr307 of PP2Ac after reperfusion were observed. We used PBA to treat the ischemia/reperfusion rat models and found that PBA could significantly reduce the expression of Bip and the phosphorylation of tau at Ser396, Ser198/199/202 phosphorylation sites. These results confirmed that ischemia/reperfusion could cause ER stress, which induce hyperphosphorylation of tau via activating GSK-3β and inhibiting PP2A.

The Activation of Excitatory Amino Acid Receptors Is Involved in tau Phosphorylation Induced by Cold Water Stress*

In order to investigate whether excitatory neurotransmission system takes roles in tau phosphorylation caused by cold water stress, mice were treated with cold water stress (CWS), which were forced to swim at 4℃ for 5 min. The tau phosphorylation in mice brains was analyzed by immunobloting and immunohistochemistry with c-fos and phosphorylation-dependent tau antibodies. To evaluate the imbalance of excitatory or inhibitory neurotransmitters system, HPLC was used to detect amino acid neurotransmitters in brain after CWS. And the phosphorylated tau in brains of CWS mice, which were pre-treated with different antagonists for excitatory amino acid receptors and L-type calcium channel, was analyzed. The phosphorylated tau in hippocampus was significantly increased accompanied by an increase of c-fos expression at 1 h after CWS. HPLC showed that the content of all detected excitatory and inhibitory amino acid neurotransmitters appeared an acute increase then decrease pattern. At 15 min after CWS, aspartate and glycine appeared a significant increase, and aspartate, glutamate, taurine and GABA significantly decreased at 1 h. When the animals were pre-treated with NMDA receptor antagonist MK-801 (5 mg/kg) and AMPA receptor antagonist DNQX (0.5, 5 mg/kg), tau phosphorylation caused by CWS were significantly suppressed. Whereas, metabolic glutamate receptor antagonist, MAP-4, had no significant effect on tau phosphorylation. In addition, L-type calcium channel blocker, nimodipine (0.05, 0.5 mg/kg), also could inhibit CWS caused tau phosphorylation. These results indicated that CWS affects tau phosphorylation by mediating excitatory neurotransmission system through ionic excitatory amino acid receptors. The activation of excitatory neurotransmission system takes roles in CWS induced tau phosphorylation in hippocampus.

Effect of amygdale-dependent learning on tau phosphorylation in hippocampus of adult rats

Effect of amygdale-dependent learning on tau phosphorylation in hippocampus of adult rats

Corticotropin-Releasing Factor Receptors Differentially Regulate Stress-Induced Tau Phosphorylation

Hyperphosphorylation of the microtubule-associated protein tau is a key event in the development of Alzheimer's disease (AD) neuropathology. Acute stress can induce hippocampal tau phosphorylation (tau-P) in rodents, but the mechanisms and pathogenic relevance of this response are unclear. Here, we find that hippocampal tau-P elicited by an acute emotional stressor, restraint, was not affected by preventing the stress-induced rise in glucocorticoids but was blocked by genetic or pharmacologic disruption of signaling through the type 1 corticotropin-releasing factor receptor (CRFR1). Conversely, these responses were exaggerated in CRFR2-deficient mice. Parallel CRFR dependence was seen in the stress-induced activation of specific tau kinases. Repeated stress exposure elicited cumulative effects on tau-P and its sequestration in an insoluble, and potentially pathogenic, form. These findings support differential regulatory roles for CRFRs in an AD-relevant form of neuronal plasticity and may link datasets documenting alterations in the CRF signaling system in AD and implicating chronic stress as a risk factor in age-related neurological disorders.