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Protective effects of BACE1 inhibitory ligand molecules against amyloid beta-induced synaptic and mitochondrial toxicities in Alzheimer's disease.

ABSTRACT: Amyloid-? (A?) peptides are the major drivers of Alzheimer's disease (AD) pathogenesis, and are formed by successive cleavage of the amyloid precursor protein (APP) by the beta and gamma secretases. Mounting evidence suggests that A? and mitochondrial structural and functional abnormalities are critically involved in the loss of synapses and cognitive decline, in patients with AD. In AD brain, state the sequential proteolytic cleavage of APP by beta secretase 1 enzyme (BACE1) and ?-secretase leads to the production and release of A?40 and 42. BACE1 expression and activity increased in the brains of AD patients. Structurally, ?-secretase has a very large binding site (1000 Å) with fewer hydrophobic domains that makes a challenge to identify the specific targets/binding sites of BACE1. In the present study, we constructed a BACE1 pharmacophore with pepstatin and screened through molecular docking studies. We found one potential candidate (referred as ligand 1) that binds to the key catalytic residues of BACE1 and predicts to inhibit abnormal APP processing and reduce A? levels in AD neurons. Using biochemical, molecular, transmission electron microscopy, immunoblotting and immunofluorescence analyses, we studied the protective effects of ligand 1 against A?-induced synaptic and mitochondrial toxicities in mouse neuroblastoma (N2a) cells that express mutant APP. We found interaction between ligand 1 and BACE1 and this interaction decreased BACE1 activity, A?40 and 42 levels. We also found increased mitochondrial biogenesis, mitochondrial fusion and synaptic activity and reduced mitochondrial fission in ligand 1-treated mutant APP cells. Based on these results, we cautiously conclude that ligand 1 reduces A?-induced mitochondrial and synaptic toxicities, and maintains mitochondrial dynamics and neuronal function in AD.

SUBMITTER: Pradeepkiran JA

PROVIDER: S-EPMC7001603 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Protective effects of BACE1 inhibitory ligand molecules against amyloid beta-induced synaptic and mitochondrial toxicities in Alzheimer's disease.

Pradeepkiran Jangampalli Adi JA Reddy Arubala P AP Yin Xiangling X Manczak Maria M Reddy P Hemachandra PH

Human molecular genetics 20200101 1

Amyloid-β (Aβ) peptides are the major drivers of Alzheimer's disease (AD) pathogenesis, and are formed by successive cleavage of the amyloid precursor protein (APP) by the beta and gamma secretases. Mounting evidence suggests that Aβ and mitochondrial structural and functional abnormalities are critically involved in the loss of synapses and cognitive decline, in patients with AD. In AD brain, state the sequential proteolytic cleavage of APP by beta secretase 1 enzyme (BACE1) and γ-secretase lea ...[more]

PMID: 31595293

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Project description:The purpose of this study is to study the neuroprotective role of selective serotonin reuptake inhibitor (SSRI), citalopram, against Alzheimer's disease (AD). Multiple SSRIs, including citalopram, are reported to treat patients with depression, anxiety and AD. However, their protective cellular mechanisms have not been studied completely. In the current study, we investigated the protective role of citalopram against impaired mitochondrial dynamics, defective mitochondrial biogenesis, defective mitophagy and synaptic dysfunction in immortalized mouse primary hippocampal cells (HT22) expressing mutant APP (SWI/IND) mutations. Using quantitative RT-PCR, immunoblotting, biochemical methods and transmission electron microscopy methods, we assessed mutant full-length APP/C-terminal fragments and Aβ levels and mRNA and protein levels of mitochondrial dynamics, biogenesis, mitophagy and synaptic genes in mAPP-HT22 cells and mAPP-HT22 cells treated with citalopram. Increased levels of mRNA levels of mitochondrial fission genes, decreased levels of fusion biogenesis, autophagy, mitophagy and synaptic genes were found in mAPP-HT22 cells relative to WT-HT22 cells. However, mAPP-HT22 cells treated with citalopram compared to mAPP-HT22 cells revealed reduced levels of the mitochondrial fission genes, increased fusion, biogenesis, autophagy, mitophagy and synaptic genes. Our protein data agree with mRNA levels. Transmission electron microscopy revealed significantly increased mitochondrial numbers and reduced mitochondrial length in mAPP-HT22 cells; these were reversed in citalopram-treated mAPP-HT22 cells. Cell survival rates were increased in citalopram-treated mAPP-HT22 relative to citalopram-untreated mAPP-HT22. Further, mAPP and C-terminal fragments werealso reduced in citalopram-treated cells. These findings suggest that citalopram reduces mutant APP and Aβ and mitochondrial toxicities and may have a protective role of mutant APP and Aβ-induced injuries in patients with depression, anxiety and AD.

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Dataset Information

Protective effects of BACE1 inhibitory ligand molecules against amyloid beta-induced synaptic and mitochondrial toxicities in Alzheimer's disease.

Publications

Protective effects of BACE1 inhibitory ligand molecules against amyloid beta-induced synaptic and mitochondrial toxicities in Alzheimer's disease.

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