Making mice Alzheimer’s without manipulating amyloid metabolism; a clue to human late-onset Alzheimer’s disease development

Alzheimer’s disease (AD) is the leading cause of cognitive impairment and death among elderly people. Underlying pathology is accumulation of neurotoxic amyloid-β protein (“plaques”) and formation of TAU protein-rich neurofibrillary “Tangles” in the brain. Late-onset AD accounts for 95% of human AD while early-onset AD accounts for 5% of human AD. Although previous studies have indicated that early onset AD is caused by mutations in genes involved in amyloid metabolism, such as Amyloid Precursor Protein (APP) and Presenilin 1 genes, the exact cause of late-onset AD has remained unknown. Numerous studies have been conducted by researchers to recapitulate the prerequisites for the occurrence of human sporadic late-onset AD in mouse models. However, no one knew how to intelligently create a mouse model that spontaneously develop late-onset AD-like pathology without directly manipulating amyloid metabolism. There is insufficient knowledge of the molecular processes that contribute to the development of late-onset AD. This limitation may have contributed to the high failure rate of AD drugs in clinical trials.

There have been recent studies indicating that aneuploidy and chromosomal instability, which often occur naturally with age, may cause or aggravate human AD. However, the causal link between aneuploidy, chromosomal instability, and AD has not been established. It is interesting to say that existing studies on Shugoshin-1 (Sgo1) haploinsufficient (∓) mouse models and BubR1 transgenic models suggest that a type of mitotic errors and chromosomal instability (called “mitotic cohesinopathy”) may facilitate AD-like accumulation of neurotoxic amyloid-β protein in the brain.

University of Oklahoma Health Sciences Center scientists: Professor Chinthalapally Rao, Mudassir Farooqui, Yuting Zhang, Adam Asch and Dr. Hiroshi Yamada demonstrated that Sgo1^-/+ haploinsufficient mouse could serve as a useful model for the preclinical investigation of spontaneous late-onset AD progression. This is actually the first report to establish a link between Shugoshin-1 and AD. The work is published in the peer-reviewed reserch journal, Aging Cell.

The authors observed that middle-aged Sgo1^-/+ expressed a higher levels of Amyloid Beta Precursor Protein-Binding Family B Member 1 (APBB1) in the blood compared to the control. They further showed accumulation of amyloid-β that colocalized with TAU, beta-secretase 1 (BACE), and mitotic marker phospho-Histone H3 (p-H3) in brains from Sgo1^-/+ mice in old age. Moreover, amyloid-β and-p-H3-positive cells were observed both in the cortex and in the hippocampus (the memory center whose function is profoundly affected by AD) of Sgo1^-/+ mice, while in wild type mice p-H3 expression was limited to the hippocampus and no amyloid-β was observed.

AD-like pathology was not observed in spindle checkpoint-defective BubR1^-/+ haploinsufficient mice. Professor Rao and colleagues also identified the abnormal expression of 10 different genes, in which 7 genes were associated with either AD pathology or neuronal functions. Their mice-based studies overall suggested involvement of a type of mitotic error in the development of late-onset AD pathology. Although further study is needed, circumstantial evidence from human AD align with the notion as well.

The study by University of Oklahoma Health Sciences Center researchers provides compelling evidence that Sgo1^-/+ haploinsufficient mouse model displays AD-like brain pathology at an age that is equivalent to old age in humans. This unique mouse model developed in their study can be used to investigate spontaneous late-onset AD progression, as well as the genetic interactions between known AD-associated genes. It is hoped the new AD mouse model will advance our knowledge on the specific mechanisms of late-onset AD pathology and the development of better drugs for AD.