Neurogenesis and Alterations of Neural Stem Cells in Mouse Models of Cerebral Amyloidosis

Abstract

The hippocampus in Alzheimer's disease is burdened with amyloid plaques and is one of the few locations where neurogenesis continues throughout adult life. To evaluate the impact of amyloid-beta deposition on neural stem cells, hippocampal neurogenesis was assessed using bromodeoxyuridine incorporation and doublecortin staining in two amyloid precursor protein (APP) transgenic mouse models. In 5-month-old APP23 mice prior to amyloid deposition, neurogenesis showed no robust difference relative to wild-type control mice, but 25-month-old amyloid-depositing APP23 mice showed significant increases in neurogenesis compared to controls. In contrast, 8-month-old amyloid-depositing APPPS1 mice revealed decreases in neurogenesis compared to controls. To study whether alterations in neurogenesis are the result of amyloid-induced changes at the level of neural stem cells, APPPS1 mice were crossed with mice expressing green fluorescence protein (GFP) under a central nervous system-specific nestin promoter. Eight-month-old nestin-GFP x APPPS1 mice exhibited decreases in quiescent nestin-positive astrocyte-like stem cells, while transient amplifying progenitor cells did not change in number. Strikingly, both astrocyte-like and transient-amplifying progenitor cells revealed an aberrant morphologic reaction toward congophilic amyloid-deposits. A similar reaction toward the amyloid was no longer observed in doublecortin-positive immature neurons. Results provide evidence for a disruption of neural stem cell biology in an amyloidogenic environment and support findings that neurogenesis is differently affected among various transgenic mouse models of Alzheimer's disease.

Exercise as a pro-cognitive, pro-neurogenic and anti-inflammatory intervention in transgenic mouse models of Alzheimer’s disease

“…Although the concept of a reduction in hippocampal neurogenesis preceding the development of A␤ plaques may account for the onset of cognitive decline, further studies are required to pinpoint exactly where alterations in hippocampal neurogenesis occur in relation to other pathologies in the development of AD. There have also been reports of increased hippocampal neurogenesis in mouse models of AD (Ermini et al, 2008;Jin et al, 2004a;Mirochnic et al, 2009;Verdaguer et al, 2015;Yu et al, 2009). It is likely that differences in animal models, the age at which they are studied, extent of A␤ pathology and method of assessment of neurogenesis, in particular BrdU administration protocols, all affect comparisons across these studies and may account for some of the differences observed with some studies reporting reductions in neurogenesis and others reporting increases.…”

Prolonged Running, not Fluoxetine Treatment, Increases Neurogenesis, but does not Alter Neuropathology, in the 3xTg Mouse Model of Alzheimer’s Disease

“…APP mice had no difference in hippocampal neurogenesis when evaluated by BrdU incorporation at young adult age. At this age the mice do not have amyloid deposits, but when the mice were evaluated at 25 months of age, APP mice exhibited significant increases in the number of BrdU and DCX-positive cells (Ermini et al 2008) while also in affected human hippocampus and cortex, proliferative and neurogenic-like changes have been seen (Boekhoorn et al 2006a; Verwer et al 2007). A separate study utilizing different APP-PS1 mice at 8 months of age showed increased BrdU and NeuN-positive cells compared to controls despite finding that APP-PS1x NestinGFP mice exhibited decreases in nonproliferative Nestin-positive NPCs (Gan et al 2008).…”

Angiotensin IV Receptors Mediate the Cognitive and Cerebrovascular Benefits of Losartan in a Mouse Model of Alzheimer's Disease

“…Memory impairment in AD mouse models has been associated with reduced hippocampal neurogenesis (Haughey et al, 2002;Zhang et al, 2007;Ermini et al, 2008). Accordingly, neurogenesis detected by BrdU labeling of newborn cells in the dentate gyrus was significantly reduced in APP mice compared with WT controls (Fig.…”