In a new study, researchers have defined the molecular mechanism that causes an accumulation of this toxic protein. Furthermore, the team showed a monoclonal antibody (mAb) that targets this toxic protein was able to prevent disease pathology and memory loss in AD- and VaD-like preclinical models. Additionally, this treatment was even capable of reversing cognitive impairment in an AD-like preclinical model.
In a preclinical model of VaD, young mice showed signs of brain inflammation and memory loss within one month. However, treating these mice with the cis P-tau mAb prevented neural degradation and cognitive decline out to six months. In a separate preclinical model of AD, old mice showed severe cognitive impairment. Excitingly, this severe impairment was significantly reversed when mice were given the cis P-tau mAb.
"These data show that cis P-tau could be an early upstream pathogenic factor common to both diseases," said Albayram.
Translating information gained from preclinical models to humans is often difficult, but this study offers reasons to be optimistic. Accumulation of cis P-tau caused dramatic changes in the genetic architecture of affected cells in a VaD model; these changes were consistent with those seen in human AD patients. The researchers went on to show that treatment with the cis P-tau mAb reversed 85% to 90 % of those changes suggesting the power of this potential therapy.
"The genomic landscape really adapts after the silencing of this toxic protein," said Albayram. "That was a big discovery."
AD and VaD might not be the only diseases affected by high levels of cis P-tau. Other brain disorders with a vascular component might also arise from this toxic protein, but further study will be required to establish such a link.
"Cis P-tau may be a common, early and pathogenic factor underlying traumatic brain injury, VaD and AD," said Qiu.
Photo: The cytotoxic tau isomer (cis P-tau; red) is partially colocalized with tau oligomers (green; top) and tau tangles (green; bottom) in Alzheimer's disease (AD) and mixed AD and VCID brains, but was detected in the absence of other tau isoforms in VCID brains. Credit: Onder Albayram of the Medical University of South Carolina.