Abstract
Rare individuals remain cognitively intact despite the presence of neuropathology usually associated with fully symptomatic Alzheimer’s disease (AD), which we refer to as Non-Demented with Alzheimer’s disease Neuropathology (NDAN). Understanding the involved mechanism(s) of their cognitive resistance may reveal novel strategies to treat AD-related dementia. In the pursuit of this goal, we determined the number of hippocampal neural stem cells (NSCs) and investigated the expression of several miRNAs in NDAN and AD subjects. Laser-capture microdissection of autopsy human hippocampus DG and qRT-PCR miRNA analyses were combined with immunofluorescence in this study. The number of SOX2+ NSCs in the DG was significantly increased in NDAN individuals as compared to AD subjects. Further, the prevalence of SOX2+ NSCs was found to correlate with cognitive capacity. Neurogenesis-regulating miRNAs were decreased in NDAN individuals as compared to AD patients. An increased number of NSCs and new neurons in NDAN individuals is associated with a unique expression of regulating miRNAs and strongly support a role of neurogenesis in mediating, in part, the ability of these individuals to resist the pathological burden of AD.
Highlights
Despite extensive research effort on Alzheimer’s disease (AD) being into its third decade[1], exactly how AD starts, how the disease progresses, and how to stop or to slow its progression are still all unresolved questions[2]
To ask whether neurogenesis is linked to preserved cognitive ability in humans with AD neuropathology, in this study we evaluated the expression of SOX2 and of the mature neuronal marker NeuN in post-mortem human tissues from Non-Demented with Alzheimer’s disease Neuropathology (NDAN), mild cognitively impaired (MCI) and AD individuals in comparison to age-matched healthy subjects
Because it is not possible to measure neurogenesis as a dynamic process in the human brain, due to the practical inability to track newborn cells and follow their differentiation over time, we used the expression of SOX2, a key regulator of neural stem cells[18,19], as an indicator of neurogenic potential in human hippocampus samples
Summary
Despite extensive research effort on Alzheimer’s disease (AD) being into its third decade[1], exactly how AD starts, how the disease progresses, and how to stop or to slow its progression are still all unresolved questions[2]. In recent years several reports have described rare individuals who remain cognitively intact despite the presence of neuropathological features usually associated with a fully symptomatic stage of AD4–9. The existence of these unusual cases, referred to as Non-Demented with Alzheimer’s disease Neuropathology (NDAN), suggests that there is a natural way for the human brain to resist (or significantly delay) the neurotoxic events that normally lead to cognitive impairment in AD. The discovery that new neurons are continuously generated in the hippocampus, an area of the brain that plays a critical role in learning and memory and is most affected by AD10, suggests that plasticity of the central nervous system could provide an endogenous protective mechanism to sustain cognitive functions. Because the differentiation and maturation of newborn neurons involves the concerted action of multiple genes, micro-RNAs (miRNA), short non-coding RNA sequences that bind to mRNA targets and inhibit their translation, have been recently identified as important regulators of neurogenesis[22,23]
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