Expression of P301L-hTau in mouse MEC induces hippocampus-dependent memory deficit

Liu, Xinghua; Zeng, Kuan; Li, Mengzhu; Wang, Qun; Liu, Rong; Zhang, Bin; Wang, Jian‐Zhi; Shu, Xin; Wang, Xiao-Chuan

doi:10.1038/s41598-017-04305-4

Cited by 10 publications

(6 citation statements)

References 47 publications

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“…However, it is not reported whether BBB affects tau transmission. Here, we constructed a rapid hTau overexpression model in mice by injecting human mutant P301L-hTau in mouse MEC [16], and then injected LPS, a common neuroinflammation inducer to destroy the integrity of BBB, through intraperitoneal of the mice. Our results indicate that BBB leakage is involved in LPS-induced hTau transmission from entorhinal cortex to hippocampus, though a causal relationship between BBB linkage and hTau transmission needs further investigation.…”

Section: Discussionmentioning

confidence: 99%

“…The cDNA encoding full-length 441-amino acid human 4-repeat tau bearing a P301L mutation with fusion protein GFP or GFP expression plasmids were cloned into a rAAV9 vector, which had been described previously [16]. Phosphate buffer saline (PBS, Hyclone); lipopolysaccharides (LPS, L2880, Sigma-Aldrich); glucocorticoid (GC, H20051748, Sinopharm).…”

Section: Reagents and Antibodiesmentioning

confidence: 99%

“…The mice were anesthetized with 2% isoflurane and subjected to a stereotaxic surgery to insert a cannula into dentate gyrus (DG). The method of microdialysis in vivo was described previously [16]. An ELISA kit was applied to measure total hTau present in microdialysis samples according to manufacturer's instructions (KHB0041, Thermo Fisher).…”

Section: In Vivo Microdialysis and Htau Assaymentioning

confidence: 99%

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Peripheral inflammation promotes brain tau transmission via disrupting blood–brain barrier

Liu

Zhang

et al. 2020

Bioscience Reports

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Abnormal aggregation of pathological tau protein is a neuropathological feature of Alzheimer’s disease (AD). In the AD patients, the abnormal tau accumulation first appeared in entorhinal cortex (EC) and then propagated to the hippocampus with microglia activation and inflammation, but the mechanism is elusive. Here, we studied the role and mechanisms underlying periphery inflammation on brain tau transmission. By intraperitoneal injection of lipopolysaccharide (LPS) with brain medial entorhinal cortex (MEC)-specific overexpressing P301L human tau (P301L-hTau), we found that both acute and chronic administration of LPS remarkably promoted P301L-hTau transmission from MEC to the hippocampal subsets. Interestingly, the chronic LPS-induced P301L-hTau transmission was still apparent after blocking microglia activation. Further studies demonstrated that LPS disrupted the integrity of blood–brain barrier (BBB) and simultaneous intraperitoneal administration of glucocorticoid (GC) attenuated LPS-promoted P301L-hTau transmission. These data together suggest that a non-microglia-dependent BBB disruption contributes to peripheral LPS-promoted brain P301L-hTau transmission, therefore, maintaining the integrity of BBB can be a novel strategy for preventing pathological tau propagation in AD and other tauopathies.

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Section: Discussionmentioning

confidence: 99%

Section: Reagents and Antibodiesmentioning

confidence: 99%

Section: In Vivo Microdialysis and Htau Assaymentioning

confidence: 99%

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Peripheral inflammation promotes brain tau transmission via disrupting blood–brain barrier

Liu

Zhang

et al. 2020

Bioscience Reports

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“…Furthermore, local inhibitory circuits in the olfactory region are impaired by oligomeric Aβ 42 peptide which disrupts olfactory information output and impairs GABAergic synaptic transmission in the olfactory system [45], resulting in neuronal hyperactivity [46,47]. There has been speculation that AD pathology might initiate and spread from the entorhinal olfactory region [48,49]. In addition, there is a known distal-inhibitory connection between the anterior cingulate cortex on the POC [43].…”

Section: Discussionmentioning

confidence: 99%

¹⁸F-FDG-PET Hyperactivity in Alzheimer’s Disease Cerebellum and Primary Olfactory Cortex

Meadowcroft

Purnell

Wang

et al. 2020

Preprint

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Cerebellar involvement in Alzheimer's disease (AD) has not been studied to the extent that cortical neuropathological changes have. Historical and recent histopathological literature demonstrate cerebellar AD pathology while functional investigation has demonstrated disrupted intrinsic cortical -cerebellar connectivity in AD. Additionally, olfactory deficits occur early in AD, prior to the onset of clinical symptoms. The neurological basis for the involvement of the cerebellum and olfactory system in the disease course remain unclear. 18 F-fludeoxyglucose (FDG) positron emission tomography (PET) data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) were analyzed to characterize metabolism in the cerebellum and olfactory region of AD, mild-cognitive impaired (MCI), and age-matched cognitively normal (CN)controls. In contrast to known parietal and temporal lobe FDG hypo-metabolism within the default mode network in AD, a significant FDG hyper-metabolism was found in the cerebellum and olfactory cortical regions (including the piriform cortex, olfactory tubercle, anterior olfactory nucleus, and nucleus accumbens shell). The increase in cerebellum glucose utilization was shown also in late-verses early-MCI patients. The cerebellar and olfactory regions both contain inhibitory distal and inter-neuronal connections that are vulnerable to disruption in AD. The hyper-metabolism in the cerebellum and olfactory structures may reflect disruption of local and system-wide inhibitory networks due to AD neurodegeneration, suggesting a hypothetical mechanism for susceptibility of the olfactory system to early AD pathology. Abbreviations:18

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“…Tau pathology propagates from one neuron to another by a process known as transsynaptic spread. When initially confined to the entorhinal cortex of C57BL/6J mice by stereotaxic injection of a viral vector encoding P301L-tau, tau pathology was reported to spread to the hippocampus and impair hippocampal-dependent LTP [39]. Likewise, tau fibrils injected into the LC of PS19 mice were found to propagate tau pathology to LC projection areas, as well as sources of LC innervation in the brain, including the hypothalamus, amygdala, bed nucleus of the stria terminalis, and frontal cortex [29].…”

Section: Propagation Of Tau Pathology From the Drn To Other Brain Reg...mentioning

confidence: 99%

Tau pathology in the dorsal raphe may be a prodromal indicator of Alzheimer’s disease

Pierson

Fiock

Wang

et al. 2022

Preprint

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Protein aggregation in brainstem nuclei is thought to occur in the early stages of Alzheimer's disease (AD), but its specific role in driving prodromal symptoms and disease progression is largely unknown. The dorsal raphe nucleus (DRN) contains a large population of serotonin (5-hydroxytryptamine; 5-HT) neurons that regulate mood, reward-related behavior, and sleep, all of which are disrupted in AD. We report here that tau pathology is present in the DRN of cognitively intact individuals 54-80 years of age, whereas synuclein and TDP-43 are relatively absent. Almost all AD cases had tau pathology in the DRN, whereas only a subset contained TDP-43 or synuclein, but not both. Mice overexpressing human P301L-tau in the DRN also exhibited depressive-like behaviors and hyperactivity without any deficits in spatial memory. There was a negative correlation between the density of Tph2-expressing neurons and phospho-tau (ptau) optical density in P301L-tauDRNmice, although mean Tph2 expression did not differ significantly from the controls. 5-HT neurons were hyperexcitable in P301L-tauDRNmice, and there was an increase in the amplitude of excitatory post-synaptic currents (EPSCs) which is suggestive of increased glutamatergic transmission. Astrocytic density was also elevated in the DRN and accompanied by an increase in GFAP expression, as well as changes inHtr2a, Htr2c,andHtr3agene expression. Additionally, tau pathology was detected in axonal processes in the thalamus, hypothalamus, amygdala, and caudate putamen, suggesting that tau may spread in an anterograde manner to regions outside the DRN. Together, these results suggest that tau pathology accumulates in the DRN in a subset of individuals over 50 years and may lead to prodromal AD symptoms, 5-HT neuronal dysfunction, and activation of local astrocytes. The presence of tau pathology in the DRN combined with psychiatric assessments for depression may be a useful screening tool for individuals at risk for AD.

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Expression of P301L-hTau in mouse MEC induces hippocampus-dependent memory deficit

Cited by 10 publications

References 47 publications

Peripheral inflammation promotes brain tau transmission via disrupting blood–brain barrier

Peripheral inflammation promotes brain tau transmission via disrupting blood–brain barrier

¹⁸F-FDG-PET Hyperactivity in Alzheimer’s Disease Cerebellum and Primary Olfactory Cortex

Tau pathology in the dorsal raphe may be a prodromal indicator of Alzheimer’s disease

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Expression of P301L-hTau in mouse MEC induces hippocampus-dependent memory deficit

Cited by 10 publications

References 47 publications

Peripheral inflammation promotes brain tau transmission via disrupting blood–brain barrier

Peripheral inflammation promotes brain tau transmission via disrupting blood–brain barrier

18F-FDG-PET Hyperactivity in Alzheimer’s Disease Cerebellum and Primary Olfactory Cortex

Tau pathology in the dorsal raphe may be a prodromal indicator of Alzheimer’s disease

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¹⁸F-FDG-PET Hyperactivity in Alzheimer’s Disease Cerebellum and Primary Olfactory Cortex