# Icaritin ameliorates mitochondrial dysfunction and autophagy impairment in cellular models of Alzheimer’s disease

## TL;DR

Icaritin, a natural compound, protects brain cells from Alzheimer’s disease by improving mitochondrial function and autophagy.

## Contribution

The study reveals a novel therapeutic mechanism of Icaritin in mitigating TDP-43-induced cellular damage in Alzheimer’s disease models.

## Key findings

- Icaritin increased cell viability and reduced Aβ42 levels in TDP-43-expressing cells.
- Icaritin improved mitochondrial function and reduced ROS levels in Alzheimer’s cellular models.
- Icaritin modulated AMPK/mTOR and PINK1/Parkin pathways to enhance autophagy.

## Abstract

Alzheimer’s disease (AD) is the most common form of dementia, characterized by progressive memory decline, with neuropathological hallmarks including amyloid plaques and neurofibrillary tangles. Current treatments only alleviate symptoms and cannot halt disease progression. Icaritin (ICT), a natural compound, has shown neuroprotective potential. Transactive response DNA-binding protein 43 (TDP-43) is widely recognized as a key neuropathological hallmark of AD and related dementias. This study investigated the protective effects of ICT against TDP-43-induced damage in N2a/APP695swe (APP) cells and explored the underlying mechanisms.

N2a/APP695swe/TARDBP cells overexpressing APP and TDP-43 were constructed via lentiviral transfection, and the optimal ICT dosage was determined using the CCK-8 assay. The effects of ICT on TDP-43 cell phenotypes were then assessed using CCK-8, ELISA, and Western blot. Finally, transmission electron microscopy, flow cytometry, assay kits, and Western blot were used to investigate the protective mechanisms of ICT.

ICT treatment significantly increased cell viability, reduced Aβ42 levels, and alleviated phospho-Tau and phospho-TDP-43 accumulation. Mechanistically, ICT improved mitochondrial morphology, decreased ROS levels, enhanced ATP production, and modulated the AMPK/mTOR and PINK1/Parkin autophagy signaling pathways to mitigate TDP-43-mediated cellular stress.

ICT protects cells from TDP-43-induced mitochondrial dysfunction and autophagy impairment, providing mechanistic insight into its potential as a therapeutic agent for AD.