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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:Amyloid-? (A?) peptides play a key role in synaptic damage and memory deficits in the early pathogenesis of Alzheimer's disease (AD). Abnormal accumulation of A? at nerve terminals leads to synaptic pathology and ultimately to neurodegeneration. ?-site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1) is the major neuronal ?-secretase for A? generation. However, the mechanisms regulating BACE1 distribution in axons and ? cleavage of APP at synapses remain largely unknown. Here, we reveal that dynein-Snapin-mediated retrograde transport regulates BACE1 trafficking in axons and APP processing at presynaptic terminals. BACE1 is predominantly accumulated within late endosomes at the synapses of AD-related mutant human APP (hAPP) transgenic (Tg) mice and patient brains. Defective retrograde transport by genetic ablation of snapin in mice recapitulates late endocytic retention of BACE1 and increased APP processing at presynaptic sites. Conversely, overexpressing Snapin facilitates BACE1 trafficking and reduces synaptic BACE1 accumulation by enhancing the removal of BACE1 from distal AD axons and presynaptic terminals. Moreover, elevated Snapin expression via stereotactic hippocampal injections of adeno-associated virus particles in mutant hAPP Tg mouse brains decreases synaptic A? levels and ameliorates synapse loss, thus rescuing cognitive impairments associated with hAPP mice. Altogether, our study provides new mechanistic insights into the complex regulation of BACE1 trafficking and presynaptic localization through Snapin-mediated dynein-driven retrograde axonal transport, thereby suggesting a potential approach of modulating A? levels and attenuating synaptic deficits in AD.SIGNIFICANCE STATEMENT ?-Site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1) trafficking and synaptic localization significantly influence its ? secretase activity and amyloid-? (A?) production. In AD brains, BACE1 is accumulated within dystrophic neurites, which is thought to augment A?-induced synaptotoxicity by A? overproduction. However, it remains largely unknown whether axonal transport regulates synaptic APP processing. Here, we demonstrate that Snapin-mediated retrograde transport plays a critical role in removing BACE1 from presynaptic terminals toward the soma, thus reducing synaptic A? production. Adeno-associated virus-mediated Snapin overexpression in the hippocampus of mutant hAPP mice significantly decreases synaptic A? levels, attenuates synapse loss, and thus rescues cognitive deficits. Our study uncovers a new pathway that controls synaptic APP processing by enhancing axonal BACE1 trafficking, thereby advancing our fundamental knowledge critical for ameliorating A?-linked synaptic pathology.

Project description:Introduction: ?-Amyloid protein (A?) putatively plays a seminal role in synaptic loss in Alzheimer's disease (AD). While there is no consensus regarding the synaptic-relevant species of A?, it is known that A? oligomers (A?Os) are noticeably increased in the early stages of AD, localizing at or within the synapse. In cell and animal models, A?Os have been shown to attach to synapses and instigate synapse dysfunction and deterioration. To establish the pathological mechanism of synaptic loss in AD, it will be important to identify the synaptic targets to which A?Os attach. Methods: An unbiased approach using far western ligand blots has identified three synaptic proteins to which A?Os specifically attach. These proteins (p100, p140, and p260) were subsequently enriched by detergent extraction, ultracentrifugation, and CHT-HPLC column separation, and sequenced by LC-MS/MS. P100, p140, and p260 were identified. These levels of A?Os targets in human AD and aging frontal cortexes were analyzed by quantitative proteomics and western-blot. The polyclonal antibody to A?Os was developed and used to block the toxicity of A?Os. The data were analyzed with one-way analysis of variance. Results: A?Os binding proteins p100, p140, and p260 were identified as Na/K-ATPase, synGap, and Shank3, respectively. ?3-Na/K-ATPase, synGap, and Shank3 proteins showed loss in the postsynaptic density (PSD) of human AD frontal cortex. In short term experiments, oligomers of A? inhibited Na/K-ATPase at the synapse. Na/K-ATPase activity was restored by an antibody specific for soluble forms of A?. ?3-Na/K-ATPase protein and synaptic ?-amyloid peptides were pulled down from human AD synapses by co-immunoprecipitation. Results suggest synaptic dysfunction in early stages of AD may stem from inhibition of Na/K-ATPase activity by A? oligomers, while later stages could hypothetically result from disrupted synapse structure involving the PSD proteins synGap and Shank3. Conclusion: We identified three A?O binding proteins as ?3-Na/K-ATPase, synGap, and Shank3. Soluble A? oligomers appear capable of attacking neurons via specific extracellular as well as intracellular synaptic proteins. Impact on these proteins hypothetically could lead to synaptic dysfunction and loss, and could serve as novel therapeutic targets for AD treatment by antibodies or other agents.

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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