A study led by Case Western Reserve University in Cleveland shows loss of a protein called nuclear factor erythroid 2-related factor 2 (NRF2) in the brain contributes to oxidative stress related corrosion and neurodegeneration in Alzheimer’s disease.
As reported in the journal PNAS, the researchers discovered that another protein, actin-associated protein Slingshot homolog-1 (SSH1), stops NRF2 from protecting the brain.
The team believes that targeting SSH1 may stop or delay the neurodegeneration seen in patients with Alzheimer’s disease. They demonstrated that blocking the action of SSH1 in lab and animal models increased the action of NRF2, limited tau and amyloid-beta accumulation and helped protect against oxidative damage, inflammation in the brain, and neurodegeneration.
Alzheimer’s disease affects almost seven million Americans over the age of 65 years and along with other dementias cost the government $345 billion a year to manage.
Oxidative brain damage begins to happen early in disease onset and it has been known for a while that NRF2 is activated to help prevent damage from oxidative stress. What was less clear was why levels of this protective protein seems to wane over time in people with Alzheimer’s.
This study shows that SSH1 is also activated by oxidative stress, but acts counter to NRF2 and gradually stops its beneficial activity by encouraging NRF2 to bind to actin and another protein called KEAP2 instead of blocking neurodegeneration.
“This offers insight into the brain’s progressive vulnerability to oxidative stress as Alzheimer’s disease advances and may provide a unique neuroprotective strategy for Alzheimer’s disease and related dementias,” write the authors.
Lead researcher and author David Kang, the Howard T. Karsner Professor in Pathology at the Case Western Reserve School of Medicine, and colleagues tested whether blocking the activity of SSH1 in mice and cell models of Alzheimer’s would reverse its negative oxidative impact. They found that NRF2 activity did increase and neurodegeneration and associated symptoms were dramatically slowed.
This research is at an early stage and needs to be further validated, but as these changes happen early on in Alzheimer’s disease progression creating a therapy to block the action of SSH1 could be very beneficial for patients.
“As most NRF2-activating drugs are electrophiles that are not well tolerated in patients, inhibiting activated SSH1 to unblock and enhance NRF2 signaling may provide an effective therapeutic strategy for neuroprotection in Alzheimer’s disease and related disorders,” conclude the authors.
“As the catalytic activity of SSH1 does not significantly contribute to NRF2 inhibition, strategies for therapeutic targeting SSH1-mediated NRF2 suppression will require innovative approaches beyond inhibiting activity at its catalytic pocket.”