Critical role of mitosis in spontaneous late-onset Alzheimer’s disease; from a Shugoshin 1 cohesinopathy mouse model

Abstract

From early-onset Alzheimer's disease (EOAD) studies, the amyloid-beta hypothesis emerged as the foremost theory of the pathological causes of AD. However, how amyloid-beta accumulation is triggered and progresses toward senile plaques in spontaneous late-onset Alzheimer's disease (LOAD) in humans remains unanswered. Various LOAD facilitators have been proposed, and LOAD is currently considered a complex disease with multiple causes. Mice do not normally develop LOAD. Possibly due to the multiple causes, proposed LOAD facilitators have not been able to replicate spontaneous LOAD in mice, representing a disease modeling issue. Recently, we reported spontaneous late-onset development of amyloid-beta accumulation in brains of Shugoshin 1 (Sgo1) haploinsufficient mice, a cohesinopathy-mediated chromosome instability model. The result for the first time expands disease relevance of mitosis studies to a major disease other than cancers. Reverse-engineering of the model would shed light on the process of late-onset amyloid-beta accumulation in the brain and spontaneous LOAD development, and contribute to development of interventions for LOAD. This review will discuss the Sgo1 model, our current "three-hit hypothesis" regarding LOAD development with an emphasis on critical role of prolonged mitosis in amyloid-beta accumulation, and implications for human LOAD intervention and treatment. Abbreviations: Alzheimer's disease (AD); Late-onset Alzheimer's disease (LOAD); Early-onset Alzheimer's disease (EOAD); Shugoshin-1 (Sgo1); Chromosome Instability (CIN); apolipoprotein (Apoe); Central nervous system (CNS); Amyloid precursor protein (APP); N-methyl-d-aspartate (NMDA); Hazard ratio (HR); Cyclin-dependent kinase (CDK); Chronic Atrial Intestinal Dysrhythmia (CAID); beta-secretase 1 (BACE); phosphor-Histone H3 (p-H3); Research and development (R&D); Non-steroidal anti-inflammatory drugs (NSAIDs); Brain blood barrier (BBB).

“Amyloid‐beta accumulation cycle” as a prevention and/or therapy target for Alzheimer's disease

“…However, most cancer assessment studies do not keep mice until old age. It was only recently that experimental results testing the link between genomic instability and AD in aged mouse models started to be reported (Rao, Farooqui, Asch, & Yamada, ).…”

“…The two‐hit hypothesis (Zhu et al, , ) proposed age and mitotic re‐entry as crucial events for development of AD pathology. In light of the apparent importance of prolonged mitosis in this process, we proposed the three‐hit hypothesis (Rao, Farooqui, Asch et al, ). The “amyloid‐beta accumulation cycle” is an integrated hypothesis that emerged from the three‐hit hypothesis.…”

“…Cohesinopathy–genomic instability model Shugoshin 1 (Sgo1) haploinsufficient mice (Sgo1 −/+ mice) showed spontaneous cerebral amyloid‐beta accumulation in old age (Figure c; Rao, Farooqui, Asch, et al, ; Rao, Farooqui, Zhang, et al, ). Normally, amyloid‐beta accumulation does not occur in mice.…”

“…However, spindle checkpoint defect–genomic instability model BubR1 −/+ mice did not show cerebral amyloid‐beta accumulation (Rao, Farooqui, Zhang et al, ), suggesting that aneuploidy alone may not be sufficient to cause amyloid‐beta accumulation in a mouse model. Since a major difference in these two chromosome instability–aneuploidogenic models is spindle checkpoint function and prolonged mitosis, prolonged mitosis was proposed to be one of the three critical factors (the “three‐hit” hypothesis; Figure b) for amyloid‐beta accumulation (Rao, Farooqui, Asch et al, ). Thus, types of aneuploidy that are accompanied by prolonged mitosis, such as cohesinopathy and amyloid‐beta poisoning, are speculated to further lead to amyloid‐beta accumulation.…”

Chromosome Instability and Mosaic Aneuploidy in Neurodegenerative and Neurodevelopmental Disorders

“…For example, Shugoshin-1 (SGO1) encodes a protein that is involved in chromosome cohesion and is needed for normal chromosome segregation, and SGO1 haploinsufficiency leads to chromosome missegregation and tumorigenesis (Yamada et al, 2012). Building on the role of aneuploidy in AD, Rao and Yamada and colleagues hypothesized that SGO1 heterozygous knockout mice may serve as a potential model of sporadic late-onset AD, and they indeed discovered some AD-related pathology as the mice aged, which was associated with prolonged mitosis and spindle checkpoint activation (Rao et al, 2018a; Rao et al, 2018b).…”