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

Jangampalli Adi Pradeepkiran, Arubala P. Reddy, Xiangling Yin, Maria Manczak, P. Hemachandra Reddy

    Research output: Contribution to journalArticle

    2 Scopus citations

    Abstract

    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 leads to the production and release of Aβ40 and 42. BACE1 expression and activity increased in the brains of AD patients. Structurally, β-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 Aβ levels in AD neurons. Using biochemical, molecular, transmission electron microscopy, immunoblotting and immunofluorescence analyses, we studied the protective effects of ligand 1 against Aβ-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, Aβ40 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 Aβ-induced mitochondrial and synaptic toxicities, and maintains mitochondrial dynamics and neuronal function in AD.

    Original languageEnglish (US)
    Pages (from-to)49-69
    Number of pages21
    JournalHuman molecular genetics
    Volume29
    Issue number1
    DOIs
    StatePublished - Jan 1 2020

    ASJC Scopus subject areas

    • Molecular Biology
    • Genetics
    • Genetics(clinical)

    Fingerprint Dive into the research topics of 'Protective effects of BACE1 inhibitory ligand molecules against amyloid beta-induced synaptic and mitochondrial toxicities in Alzheimer's disease'. Together they form a unique fingerprint.

  • Cite this