Sequential targeting nanochaperone disrupts Aβ-Ca2+-ROS feedback loop, alleviating Alzheimer's in mice

Alzheimer's disease (AD) is a devastating neurodegenerative condition characterized by cognitive decline and neuronal loss. A central pathogenic mechanism is mitochondrial dysfunction, which forms a self-perpetuating feedback loop involving upstream β-amyloid protein (Aβ), downstream calcium ion (Ca2+) dyshomeostasis, and reactive oxygen species (ROS) overload. Current therapeutic strategies often target only one aspect of this complex cycle or lack specific targeting to damaged neuronal mitochondria, limiting their efficacy in breaking this vicious cycle.

Researchers developed a sequential targeting nanochaperone designed to selectively target damaged neuronal mitochondria. The nanochaperone was decorated with a sequence of damaged neuron-targeting and mitochondria-targeting peptides on its surface. This design allowed it to first localize to damaged neurons in the 5xFAD transgenic mouse brain and then translocate specifically to their mitochondria. The nanochaperone's mechanism involved chaperone-mimicking microdomains and an Aβ-targeting peptide to bind and inhibit Aβ aggregation, alongside a modified mitochondria-targeting peptide with antioxidant properties to scavenge ROS and regulate Ca2+ homeostasis.

The sequential targeting nanochaperone demonstrated remarkable efficacy in disrupting the mitochondrial dysfunction feedback loop in 5xFAD transgenic mice. It effectively bound upstream Aβ proteins, inhibiting their aggregation toxicity to mitochondria. This action successfully halted downstream mitochondrial Ca2+ dyshomeostasis and ROS overload within damaged neurons. Furthermore, the modified mitochondria-targeting peptide's antioxidant property actively scavenged overproduced ROS and regulated Ca2+ homeostasis, further reducing Aβ-induced mitochondrial damage. The combined effects led to a significant restoration of mitochondrial function. > The nanochaperone efficiently restored mitochondrial dysfunction by disrupting the self-amplifying feedback loop of "Aβ-Ca2+-ROS" in the AD mitochondrial microenvironment, resulting in the significant alleviation of neuronal damage and cognitive deficits in 5xFAD transgenic mice.