RESUMEN
Whether hippocampal neurogenesis persists throughout life in the human brain is not fully resolved. Here, we demonstrate that hippocampal neurogenesis is persistent through the tenth decade of life and is detectable in patients with mild cognitive impairments and Alzheimer's disease. In a cohort of 18 participants with a mean age of 90.6 years, Nestin+Sox2+ neural progenitor cells (NPCs) and DCX+ neuroblasts and immature neurons were detected, but their numbers greatly varied between participants. Nestin+ cells localize in the anterior hippocampus, and NPCs, neuroblasts, and immature neurons are evenly distributed along the anterior to posterior axis. The number of DCX+PCNA+ cells is reduced in mild cognitive impairments, and higher numbers of neuroblasts are associated with better cognitive status. The number of DCX+PCNA+ cells correlates with functional interactions between presynaptic SNARE proteins. Our results suggest that hippocampal neurogenesis persists in the aged and diseased human brain and that it is possibly associated with cognition.
Asunto(s)
Envejecimiento/fisiología , Enfermedad de Alzheimer/patología , Hipocampo/patología , Células-Madre Neurales/fisiología , Neuronas/fisiología , Anciano de 80 o más Años , Células Cultivadas , Cognición , Estudios de Cohortes , Proteínas de Dominio Doblecortina , Proteína Doblecortina , Femenino , Humanos , Masculino , Proteínas Asociadas a Microtúbulos/metabolismo , Nestina/metabolismo , Neurogénesis , Neuropéptidos/metabolismo , Antígeno Nuclear de Célula en Proliferación/metabolismo , Proteínas SNARE/metabolismo , Factores de Transcripción SOXB1/metabolismoRESUMEN
BACKGROUND: The molecular mechanism underlying progressive memory loss in Alzheimer's disease is poorly understood. Neurogenesis in the adult hippocampus is a dynamic process that continuously changes the dentate gyrus and is important for hippocampal plasticity, learning and memory. However, whether impairments in neurogenesis affect the hippocampal circuitry in a way that leads to memory deficits characteristic of Alzheimer's disease is unknown. Controversial results in that regard were reported in transgenic mouse models of amyloidosis. METHODS: Here, we conditionally ablated adult neurogenesis in APPswe/PS1ΔE9 mice by crossing these with mice expressing nestin-driven thymidine kinase (δ-HSV-TK). RESULTS: These animals show impairment in performance in contextual conditioning and pattern separation tasks following depletion of neurogenesis. Importantly, these deficits were not observed in age-matched APPswe/PS1ΔE9 or δ-HSV-TK mice alone. Furthermore, we show that cognitive deficits were accompanied by the upregulation of hyperphosphorylated tau in the hippocampus and in immature neurons specifically. Interestingly, we observed upregulation of the immediate early gene Zif268 (Egr-1) in the dentate gyrus, CA1 and CA3 regions of the hippocampus following learning in the neurogenesis-depleted δ-HSV-TK mice. This may suggest overactivation of hippocampal neurons in these areas following depletion of neurogenesis. CONCLUSIONS: These results imply that neurogenesis plays an important role in the regulation of inhibitory circuitry of the hippocampus. This study suggests that deficits in adult neurogenesis may contribute to cognitive impairments, tau hyperphosphorylation in new neurons and compromised hippocampal circuitry in Alzheimer's disease.