Summary: Researchers examined the role of the BMI1 gene in the onset and progression of Alzheimer’s disease. Their results suggest that reduced BMI1 expression can trigger increased amyloid‑beta and tau production and impair neuronal clearance of toxic proteins.

Source: University of Montreal

New Insights into the Origins of Late‑Onset Alzheimer’s Disease

After more than a decade of research, a team led by Dr. Gilbert Bernier of Hôpital Maisonneuve‑Rosemont and the Université de Montréal reports findings that shed light on the potential origins of the most common form of Alzheimer’s disease (AD). Their study, published in Cell Reports, focuses on the epigenetic regulation of the BMI1 gene and its role in late‑onset sporadic AD.

Why this matters

Alzheimer’s disease becomes increasingly common with age: roughly one in two people over 90 show some degree of AD. While early‑onset familial AD can be traced to specific genetic mutations, the cause of the more prevalent late‑onset sporadic AD remains poorly understood. Age is the primary risk factor, and researchers have sought to identify genetic and epigenetic changes that might explain why the aging brain becomes susceptible to the pathological features of AD.

Investigating BMI1: an epigenetic candidate

Dr. Bernier and colleagues began from the hypothesis that epigenetic changes—alterations in gene function without changes to DNA sequence—contribute to late‑onset AD. They focused on BMI1, a gene known to maintain transcriptional repression of developmental genes through histone modification. Prior studies in mice showed that BMI1 deficiency caused accelerated brain aging and neurodegeneration, prompting the team to investigate whether similar changes occur in human AD.

Patient brain tissue and neuronal models

The researchers analyzed post‑mortem brain tissue from patients with late‑onset AD and compared it to tissue from age‑matched individuals without AD. They observed a pronounced reduction in BMI1 expression exclusively in brains from the late‑onset AD group. To rule out the possibility that BMI1 reduction was simply a consequence of disease, they examined brains from individuals with early‑onset familial AD and other age‑related dementias, including frontotemporal dementia and Lewy body dementia. In these cases, BMI1 expression was not reduced.

To further validate these findings, the team generated induced pluripotent stem cell (iPSC)‑derived cortical neurons from several AD patients and healthy controls. BMI1 expression was reduced in neurons derived from late‑onset AD patients but not in neurons overexpressing mutant APP and PSEN1 associated with familial AD. These results supported the idea that BMI1 loss is specifically associated with the common sporadic form of AD and may precede or contribute to disease onset rather than merely result from neurodegeneration.

Modeling BMI1 deficiency in human neurons

To test causality, investigators created mature, healthy human neurons in vitro and used genetic methods to silence BMI1. Strikingly, BMI1-deficient neurons developed the key neuropathological features of AD: increased secretion and deposition of amyloid‑beta (Aβ42) and accumulation of phosphorylated tau (p‑Tau), together with signs of neuronal dysfunction and degeneration. These findings indicate that loss of BMI1 alone is sufficient to induce several hallmarks of Alzheimer’s pathology in human neurons.

Mechanisms linking BMI1 loss to pathology

Molecular analyses showed that BMI1 deficiency leads to multiple changes that promote neurodegeneration. Loss of BMI1 increased production of amyloid‑beta and tau proteins and reduced neurons’ ability to clear toxic proteins. Mechanistically, BMI1 normally represses transcription of the MAPT gene (which encodes tau) and helps prevent stabilization of proteins such as GSK3β and p53 that are implicated in tau phosphorylation and neuronal stress responses. When BMI1 is reduced, these regulatory controls fail, favoring accumulation of toxic protein species and neuronal damage.

Implications and therapeutic potential

These results suggest that restoring BMI1 function in neurons at early stages of late‑onset AD could potentially mitigate or even reverse disease progression. Based on this idea, researchers associated with the study established a company in 2016 with the goal of developing therapeutics that target BMI1 pathways. While further research and clinical validation are required, the findings point to BMI1 as a promising target for intervention in sporadic late‑onset Alzheimer’s disease.

Funding and research context

Funding for the study was provided by the Canadian Institutes of Health Research and the Natural Sciences and Engineering Research Council of Canada. The work was conducted by a team including Anthony Flamier, Jida El Hajjar, James Adjaye, Karl J. Fernandes, Mohamed Abdouh, and Gilbert Bernier and was published as “Modeling Late‑Onset Sporadic Alzheimer’s Disease through BMI1 Deficiency” in Cell Reports (published May 29, 2018). DOI: 10.1016/j.celrep.2018.04.097.

Abstract (concise)

Late‑onset sporadic Alzheimer’s disease is the most common form of dementia, but its origin is unclear. BMI1, part of a protein complex that maintains transcriptional repression via histone modification, is reduced in late‑onset AD brains and in cortical neurons derived from AD patient iPSCs. BMI1 deficiency in human post‑mitotic neurons causes secretion and deposition of amyloid‑beta, accumulation of phosphorylated tau, and neurodegeneration. BMI1 represses MAPT transcription and limits stabilization of GSK3β and p53; loss of BMI1 leads to pathways that promote neurodegeneration. Restoring BMI1 activity genetically or pharmacologically represents a potential therapeutic strategy against late‑onset AD.

Highlights

• BMI1 expression is reduced in late‑onset AD brains but not in familial AD, frontotemporal dementia, or Lewy body dementia.
• BMI1 is reduced in iPSC‑derived cortical neurons from multiple late‑onset AD patients.
• BMI1 deficiency in human neurons leads to Aβ42 secretion and p‑Tau accumulation.
• BMI1 represses MAPT transcription and prevents stabilization of GSK3β and p53, mechanisms linked to neurodegeneration.

Publisher: NeuroscienceNews summary of University of Montreal research.