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Synapsin 1 promotes A? generation via BACE1 modulation.

ABSTRACT: It has been revealed that ?-amyloid (A?) is generated and released from the presynaptic terminals in activity-dependent manner. However, molecules modulating the presynaptic A? generation remain elusive. Here we test the hypothesis that Synapsin 1 (Syn1) may acts as a modulator of the A? production. Using biochemical and Förster resonance energy transfer (FRET)-based imaging approaches we have found that Syn1 knock down decreases, whereas (over)expression of Syn1 in cells increases the A? levels. Mechanistically, Syn1 does not seem to affect the activity of Presenilin 1 (PS1)/?-secretase, PS1 conformation, or the proximity between PS1 and amyloid precursor protein (APP). However, we found that Syn1 is involved in up-regulation of the ?-site APP cleaving enzyme 1 (BACE1)/?-secretase activity and increases the APP/BACE1 interaction. Therefore, we conclude that Syn1 may promote A? production via the modulation of BACE1.

SUBMITTER: Maesako M

PROVIDER: S-EPMC6907790 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Synapsin 1 promotes Aβ generation via BACE1 modulation.

Maesako Masato M Zoltowska Katarzyna M KM Berezovska Oksana O

PloS one 20191212 12

It has been revealed that β-amyloid (Aβ) is generated and released from the presynaptic terminals in activity-dependent manner. However, molecules modulating the presynaptic Aβ generation remain elusive. Here we test the hypothesis that Synapsin 1 (Syn1) may acts as a modulator of the Aβ production. Using biochemical and Förster resonance energy transfer (FRET)-based imaging approaches we have found that Syn1 knock down decreases, whereas (over)expression of Syn1 in cells increases the Aβ levels ...[more]

PMID: 31830091

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Project description:Glucocorticoid has been widely accepted to induce Alzheimer's disease, but the nongenomic effect of glucocorticoid on amyloid β (Aβ) generation has yet to be studied. Here, we investigated the effect of the nongenomic pathway induced by glucocorticoid on amyloid precursor protein processing enzymes as well as Aβ production using male ICR mice and human neuroblastoma SK-N-MC cells. Mice groups exposed to restraint stress or intracerebroventricular injection of Aβ showed impaired cognition, decreased intracellular glucocorticoid receptor (GR) level, but elevated level of membrane GR (mGR). In this respect, we identified the mGR-dependent pathway evoked by glucocorticoid using impermeable cortisol conjugated to BSA (cortisol-BSA) on SK-N-MC cells. Cortisol-BSA augmented the expression of β-site amyloid precursor protein cleaving enzyme 1 (BACE1), the level of C-terminal fragment β of amyloid precursor protein (C99) and Aβ production, which were maintained even after blocking intracellular GR. We also found that cortisol-BSA enhanced the interaction between mGR and Gαs, which colocalized in the lipid raft. The subsequently activated CREB by cortisol-BSA bound to the CRE site of the BACE1 promoter increasing its expression, which was downregulated by inhibiting CBP. Consistently, blocking CBP attenuated cognitive impairment and Aβ production induced by corticosterone treatment or intracerebroventricular injection of Aβ more efficiently than inhibiting intracellular GR in mice. In conclusion, glucocorticoid couples mGR with Gαs and triggers cAMP-PKA-CREB axis dependent on the lipid raft to stimulate BACE1 upregulation and Aβ generation.SIGNIFICANCE STATEMENT Patients with Alzheimer's disease (AD) have been growing sharply and stress is considered as the major environment factor of AD. Glucocorticoid is the primarily responsive factor to stress and is widely known to induce AD. However, most AD patients usually have impaired genomic pathway of glucocorticoid due to intracellular glucocorticoid receptor deficiency. In this respect, the genomic mechanism of glucocorticoid faces difficulties in explaining the consistent amyloid β (Aβ) production. Therefore, it is necessary to investigate the novel pathway of glucocorticoid on Aβ generation to find a more selective therapeutic approach to AD patients. In this study, we revealed the importance of nongenomic pathway induced by glucocorticoid where membrane glucocorticoid receptor plays an important role in Aβ formation.

Project description:Alzheimer's disease (AD) is characterized by amyloid plaques composed of the β-amyloid (Aβ) peptide surrounded by swollen presynaptic dystrophic neurites consisting of dysfunctional axons and terminals that accumulate the β-site amyloid precursor protein (APP) cleaving enzyme (BACE1) required for Aβ generation. The cellular and molecular mechanisms that govern presynaptic dystrophic neurite formation are unclear, and elucidating these processes may lead to novel AD therapeutic strategies. Previous studies suggest Aβ may disrupt microtubules, which we hypothesize have a critical role in the development of presynaptic dystrophies. To investigate this further, here we have assessed the effects of Aβ, particularly neurotoxic Aβ42, on microtubules during the formation of presynaptic dystrophic neurites in vitro and in vivo. Live-cell imaging of primary neurons revealed that exposure to Aβ42 oligomers caused varicose and beaded neurites with extensive microtubule disruption, and inhibited anterograde and retrograde trafficking. In brain sections from AD patients and the 5XFAD transgenic mouse model of amyloid pathology, dystrophic neurite halos with BACE1 elevation around amyloid plaques exhibited aberrant tubulin accumulations or voids. At the ultrastructural level, peri-plaque dystrophies were strikingly devoid of microtubules and replete with multi-lamellar vesicles resembling autophagic intermediates. Proteins of the microtubule motors, kinesin and dynein, and other neuronal proteins were aberrantly localized in peri-plaque dystrophies. Inactive pro-cathepsin D also accumulated in peri-plaque dystrophies, indicating reduced lysosomal function. Most importantly, BACE1 accumulation in peri-plaque dystrophies caused increased BACE1 cleavage of APP and Aβ generation. Our study supports the hypothesis that Aβ induces microtubule disruption in presynaptic dystrophic neurites that surround plaques, thus impairing axonal transport and leading to accumulation of BACE1 and exacerbation of amyloid pathology in AD.

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Synapsin 1 promotes A? generation via BACE1 modulation.

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Synapsin 1 promotes Aβ generation via BACE1 modulation.

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