Amelioration of Alzheimer’s disease pathology by mitophagy inducers identified via machine learning and a cross-species workflow

Abstract

A reduced removal of dysfunctional mitochondria is common to aging and age-related neurodegenerative pathologies such as Alzheimer’s disease (AD). Strategies for treating such impaired mitophagy would benefit from the identification of mitophagy modulators. Here we report the combined use of unsupervised machine learning (involving vector representations of molecular structures, pharmacophore fingerprinting and conformer fingerprinting) and a cross-species approach for the screening and experimental validation of new mitophagy-inducing compounds. From a library of naturally occurring compounds, the workflow allowed us to identify 18 small molecules, and among them two potent mitophagy inducers (Kaempferol and Rhapontigenin). In nematode and rodent models of AD, we show that both mitophagy inducers increased the survival and functionality of glutamatergic and cholinergic neurons, abrogated amyloid-β and tau pathologies, and improved the animals’ memory. Our findings suggest the existence of a conserved mechanism of memory loss across the AD models, this mechanism being mediated by defective mitophagy. The computational–experimental screening and validation workflow might help uncover potent mitophagy modulators that stimulate neuronal health and brain homeostasis.

P. edulis Extract Protects Against Amyloid-β Toxicity in Alzheimer’s Disease Models Through Maintenance of Mitochondrial Homeostasis via the FOXO3/DAF-16 Pathway

“…Transgenic nematodes expressing hAβ 1−42 and hTau[P301L] displayed severe cognitive de cits and neurodegeneration as we [10,27] and others [28,29] reported before. We administrated PEP at 250 µg/ml to the nematodes from egg hatching onwards and performed memory experiments on adult Day 1.…”

“…Epidemiological studies indicate that AD not only impairs memory but also shortens lifespan [30,31]. We postulated that strategies that improve memory in animals with AD could also extend their lifespan [27]. Therefore, we subsequently assess the potential effect of PEP on lifespan in the transgenic nematode models of AD.…”

Urolithin A attenuates auditory cell senescence by activating mitophagy

“…Mitophagy maintains neuronal function through maintaining a healthy mitochondrial population and efficient energy supply in the nervous system 23 . Mitophagy inducers such as Kaempferol and Rhapontigenin inhibited memory loss in nematode and rodent models of Alzheimer’s disease through the elimination of dysfunctional mitochondria 24 . Induction of mitophagy through NAD + augmentation forestalled Alzheimer’s disease, Parkinson’s disease, and Huntington disease in animal and cell culture models 25 .…”

Altered Mitochondrial Protein Homeostasis and Proteinopathies

“…Recovery of mitophagic function via NAD + supplementation, PINK1 overexpression, urolithin A, or actinonin recovers some aspects of AD pathology, such as reducing levels of insoluble amyloid beta, reducing levels of hyperphosphorylated tau, and preventing cognitive impairment ( Du et al, 2017 ; Fang et al, 2019 ). Small molecule mitophagy inducers similarly increase functionality of glutamatergic and cholinergic neurons, and reduce protein aggregation ( Xie et al, 2022 ).…”