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Signaling via the p75 neurotrophin receptor facilitates amyloid-?-induced dendritic spine pathology.

ABSTRACT: Synapse and dendritic spine loss induced by amyloid-? oligomers is one of the main hallmarks of the early phases of Alzheimer's disease (AD) and is directly correlated with the cognitive decline typical of this pathology. The p75 neurotrophin receptor (p75^NTR) binds amyloid-? oligomers in the nM range. While it was shown that µM concentrations of amyloid-? mediate cell death, the role and intracellular signaling of p75^NTR for dendritic spine pathology induced by sublethal concentrations of amyloid-? has not been analyzed. We describe here p75^NTR as a crucial binding partner in mediating effects of soluble amyloid-? oligomers on dendritic spine density and structure in non-apoptotic hippocampal neurons. Removing or over-expressing p75^NTR in neurons rescues or exacerbates the typical loss of dendritic spines and their structural alterations observed upon treatment with nM concentrations of amyloid-? oligomers. Moreover, we show that binding of amyloid-? oligomers to p75^NTR activates the RhoA/ROCK signaling cascade resulting in the fast stabilization of the actin spinoskeleton. Our results describe a role for p75^NTR and downstream signaling events triggered by binding of amyloid-? oligomers and causing dendritic spine pathology. These observations further our understanding of the molecular mechanisms underlying one of the main early neuropathological hallmarks of AD.

SUBMITTER: Patnaik A

PROVIDER: S-EPMC7415136 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Signaling via the p75 neurotrophin receptor facilitates amyloid-β-induced dendritic spine pathology.

Patnaik Abhisarika A Zagrebelsky Marta M Korte Martin M Holz Andreas A

Scientific reports 20200807 1

Synapse and dendritic spine loss induced by amyloid-β oligomers is one of the main hallmarks of the early phases of Alzheimer's disease (AD) and is directly correlated with the cognitive decline typical of this pathology. The p75 neurotrophin receptor (p75<sup>NTR</sup>) binds amyloid-β oligomers in the nM range. While it was shown that µM concentrations of amyloid-β mediate cell death, the role and intracellular signaling of p75<sup>NTR</sup> for dendritic spine pathology induced by sublethal c ...[more]

PMID: 32770070

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Project description:BackgroundAlzheimer's disease (AD) is the most common neurodegenerative disease worldwide but has no effective treatment. Amyloid beta (Aβ) protein, a primary risk factor for AD, accumulates and aggregates in the brain of patients with AD. Paired immunoglobulin-like receptor B (PirB) has been identified as a receptor of Aβ and Aβ-PirB molecular interactions that cause synapse elimination and synaptic dysfunction. PirB deletion has been shown to suppress Aβ-induced synaptic dysfunction and behavioral deficits in AD model mice, implying that PirB mediates Aβ-induced AD pathology. Therefore, inhibiting the Aβ-PirB molecular interaction could be a successful approach for combating AD pathology. We previously showed that lateral olfactory tract usher substance (LOTUS) is an endogenous antagonist of type1 Nogo receptor and PirB and that LOTUS overexpression promotes neuronal regeneration following damage to the central nervous system, including spinal cord injury and ischemic stroke. Therefore, in this study, we investigated whether LOTUS inhibits Aβ-PirB interaction and Aβ-induced dendritic spine elimination.MethodsThe inhibitory role of LOTUS against Aβ-PirB (or leukocyte immunoglobulin-like receptor subfamily B member 2: LilrB2) binding was assessed using a ligand-receptor binding assay in Cos7 cells overexpressing PirB and/or LOTUS. We assessed whether LOTUS inhibits Aβ-induced intracellular alterations and synaptotoxicity using immunoblots and spine imaging in a primary cultured hippocampal neuron.ResultsWe found that LOTUS inhibits the binding of Aβ to PirB overexpressed in Cos7 cells. In addition, we found that Aβ-induced dephosphorylation of cofilin and Aβ-induced decrease in post-synaptic density-95 expression were suppressed in cultured hippocampal neurons from LOTUS-overexpressing transgenic (LOTUS-tg) mice compared with that in wild-type mice. Moreover, primary cultured hippocampal neurons from LOTUS-tg mice improved the Aβ-induced decrease in dendritic spine density. Finally, we studied whether human LOTUS protein inhibits Aβ binding to LilrB2, a human homolog of PirB, and found that human LOTUS inhibited the binding of Aβ to LilrB2 in a similar manner.ConclusionsThis study implied that LOTUS improved Aβ-induced synapse elimination by suppressing Aβ-PirB interaction in rodents and inhibited Aβ-LilrB2 interaction in humans. Our findings revealed that LOTUS may be a promising therapeutic agent in counteracting Aβ-induced AD pathologies.

Dataset Information

Signaling via the p75 neurotrophin receptor facilitates amyloid-?-induced dendritic spine pathology.

Publications

Signaling via the p75 neurotrophin receptor facilitates amyloid-β-induced dendritic spine pathology.

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