Research Spotlight | Abnormal Accumulation of pTau Protein Destroys the Microenvironment of Hippocampal Neurogenesis

2020-11-20Author:adminpraise:0

Researchers from Professor Jianzhi Wang’s team reported that human tau accumulation in dentate gyrus GABAergic interneurons disrupts AHN and strengthening GABAergic signaling restores AHN and improves cognition in an AD mouse model, this study also suggests potential therapeutic avenues that could alleviate AD related AHN deficits.

Fundamental Information

Title: Interneuron Accumulation of Phosphorylated tau Impairs Adult Hippocampal Neurogenesis by Suppressing GABAergic Transmission

Journal: Cell Stem Cell

Impact Factor: 20.86(2019)

Institution of the first author: Huazhong University of Science and Technology

Institution of the corresponding author: Huazhong University of Science and Technology

Elabscience® Products Cited

Cat. No

Application

Detection target

Species

Tested sample

E-EL-H0542

ELISA

Aβ1-40 (Amyloid Beta 1-40)

Mice

Hippocampal tissues

E-EL-H0543

ELISA

Aβ1-42 (Amyloid Beta 1-42)

Mice

Hippocampal tissues



Background

Dementia due to Alzheimer’s disease (AD) is general in senior citizens. Targeting β-amyloid (Aβ) and tau have been proved to suitable remedies in stopping AD progression. A remarkable decline of adult hippocampal neurogenesis (AHN) was observed in AD patients and animals and this decline seems to occur even before the onset of AD. Understanding how the fate of AHN is determined by AD pathological factors is cardinal for efficiently introducing neurogenesis, from either innate or grafted NSCs. Tau pathology is crucial in AD progression. Given the important role of GABAergic tempos in maintaining the NSC quiescence and shaping AHN, it was hypothesized that tau accumulation, especially that in GABAergic interneurons, contributes to the AHN deficits in AD brains through dysregulating GABAergic transmissions and disrupting neural network dynamics in the hippocampal neurogenic niche.

Purpose of research

1. To investigate how hTau aggregation dysregulates AHN in AD.

2. To explore how human tau (hTau) accumulation in DG GABAergic interneurons affects AHN

Experimental design

In this study, human brain sections, mice model, and in vitro experiments were used to determine impairment of interneuron accumulation of phosphorylated Tau for adult hippocampal neurogenesis by suppressing GABAergic transmission.

Research Findings

1. A remarkable accumulation of pTau was observed in the SGZ and hilus of AD patients and AD mice. And the majority of those pTau-positive cells was identified as GABAergic interneurons by co-labeling with glutamate decarboxylase 67 (GAD67), parvalbumin (PV), and somatostatin (SST).

2.Specific overexpressing hTau in GABAergic interneurons induces multiple AHN deficits in  mice, also selective hTau overexpression in PV and SST interneurons resulted in comparable deficits of AHN, reducing BrdU- and DCX-labeled cell number and deceased the dendrite length, complexity, and spine density.

3.Overexpression of hTau in GABAergic interneurons increased NSC-derived astrogliosis and impaired neurogenesis.


4.Interneuron hTau overexpression significantly changed the expression or phosphorylation of various proteins involved in general, glutamatergic, or GABAergic synaptic transmissions.

5. It was found that interneuron contributed in hTau-accumulation-induced neural network hyperactivation to the AHN deficits, which can be partly rescued by chemogenic inhibition of local excitatory neurons

1) hTau-induced neural network hyperactivation was a result of impairment in GABAergic transmission. Interneuron hTau overexpression significantly attenuated GABAergic responses (taken 5% DF/F as the threshold) in the Dentate Gyrus.

2) Reduction of phospho-GAD67 (pGAD67) might dysregulate GABA synthesis and finally lead to the reduction of GABA

6. Strengthening GABAergic transmission by THIP could rescue the interneuron hTau-induced AHN deficits and ameliorate AHN deficits and cognitive impairment in AD mice.



Conclusions and Innovations

1. It was found that Phospho-tau accumulation in DG GABAergic interneurons of both AD patients and mice.

2. The interneuron overexpressing hTau impairs hippocampal neurogenesis by suppressing GABAergic transmissions, disinhibiting local neuronal circuits and promoting astrogliosis.

3. THIP, a δ-GABAAR agonist can improve neurogenesis and cognition in AD mice

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