Editors' ChoiceAlzheimer's Disease

Neurogenesis takes a hit in Alzheimer’s disease

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Science Translational Medicine  01 May 2019:
Vol. 11, Issue 490, eaax1726
DOI: 10.1126/scitranslmed.aax1726


New neurons are born in healthy humans throughout aging but decline in Alzheimer's disease, linking a loss of neurogenesis with disease progression.

For over a century a central dogma of neuroscience prevailed, implicating the lack of neurogenesis in the adult mammalian brain. This view was based on the belief that the adult brain is a static network requiring precision and stability between fixed neuronal connections whose modulation may result in profound behavioral or memory changes. This dogma was finally challenged in 1965 when it was discovered that new neurons are born in the adult hippocampus of rodents. Over the ensuing decades, neurogenesis was demonstrated in several mammals, including humans.

These studies and others established neurogenesis as a cellular mechanism; however, its relevance to human health and disease has remained elusive. By developing a state-of-the-art tissue processing method Moreno-Jimenez et al. provided evidence that neurogenesis persists throughout aging in healthy humans at an extent previously undetected by conventional procedures. The authors identified thousands of neurons expressing doublecortin, a marker for neurogenesis, in the hippocampal dentate gyrus from neurologically healthy subjects up to the ninth decade of life. Histological analyses revealed these neurons exhibited variable degrees of maturation; a subset of neurons expressed the calcium binding protein calretinin, a marker for the early phase of neurogenesis, whereas others expressed the calcium binding protein calbindin, a maker for differentiated dentate granule cells. Using this tightly regulated process for tissue processing, the authors investigated the role of neurogenesis in Alzheimer’s disease (AD) the most common form of dementia. Analysis of AD brains at various stages of the disease revealed a progressive decline in neurogenesis as the disease advanced. Further, this decline was evident at early disease before overt AD-related pathologies and was accompanied by a substantial impairment of neuronal maturation.

Although this study demonstrates new neurons are born throughout aging in healthy humans, their synaptic activity and functionality remains unknown. Moreover, a daunting task will be to determine the role of neurogenesis in learning and memory in humans. Nonetheless, the decline in neurogenesis in AD suggests it may be an early contributor to the disease progression and therapeutic strategies aimed at increasing neurogenesis may slow the disease. These findings also suggest that the diseased brain provides an inadequate environment for neurogenesis even in the absence of profound AD-related neuropathology, suggesting that contributing factors to AD progression remain to be discovered. Last, it is important to take into consideration the common procedures used routinely for the preparation of human samples as this may lead to a reduction in tissue integrity, limiting the discovery of pathological contributors of AD and other neurological disorders.

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