Genomic mosaicism with increased amyloid precursor protein (APP) gene copy number in single neurons from sporadic Alzheimer's disease brains

摘要

The instructions for living cells are contained in certain stretches of DNA, called genes, and these instructions have been largely considered to be invariant, such that every cell in the body has the same DNA. However, research has revealed that many neurons in the human brain can contain different amounts of DNA compared to other cells. When cells with varied DNA are present in the same person, it is referred to as mosaicism. The effects of this mosaicism are unknown, although by altering the instructions in brain cells, it is suspected to influence both the normal and diseased brain. The brains of patients with Alzheimer's disease often contain deposits of proteins called amyloids. The precursor of the protein that makes up most of these deposits is produced from a gene called the amyloid precursor protein gene, or APP. Having an extra copy of the APP gene can cause rare ‘familial’ Alzheimer's disease, wherein the APP duplication can be passed on genetically and is present in all the cells of a patient's body. By contrast, ‘sporadic’ Alzheimer's disease, which constitutes around 95% of cases, does not show any difference in the number of APP genes found in tissue samples, including whole brain. The early studies that discovered this were conducted before an appreciation of brain mosaicism, and thus single neurons were not investigated. This raises the possibility that the number of APP genes may be mosaically increased, which would not be detected by examining non-brain or bulk brain tissue. Bushman, Kaeser et al. used five different types of experiments to examine the DNA content of single neurons and investigate whether mosaicism could explain the discrepancy in the results of the previous studies. The neurons from people with Alzheimer's disease contained more DNA—on average, hundreds of millions of DNA base pairs more—and more copies of the APP gene, with some neurons containing up to 12 copies. Bushman, Kaeser et al.'s findings present evidence of a way that mosaicism can affect how the brain works by altering the number of gene copies, and how this impacts the most common form of Alzheimer's disease. Many questions arise from the work, including when does mosaicism arise, and what promotes its formation? How does this relate to age? What parts of the genome are changed, what genes are affected, and how do these changes alter neuronal function? Furthermore, Bushman, Kaeser et al.'s work suggests that mosaicism may also play a role in other brain diseases, and could also provide new insights into the normal, complex functions of the brain. In the future, this knowledge could help to identify new treatments for brain diseases; for example, by identifying new molecular targets for therapy hidden in the extra DNA or by understanding how to alter mosaicism.