Enhanced neurogenesis in Alzheimer's disease transgenic (PDGF-APPSw,Ind) mice

Abstract

Neurogenesis continues in the adult brain and is increased in certain pathological states. We reported recently that neurogenesis is enhanced in hippocampus of patients with Alzheimer's disease (AD). We now report that the effect of AD on neurogenesis can be reproduced in a transgenic mouse model. PDGF-APP(Sw,Ind) mice, which express the Swedish and Indiana amyloid precursor protein mutations, show increased incorporation of BrdUrd and expression of immature neuronal markers in two neuroproliferative regions: the dentate gyrus and subventricular zone. These changes, consisting of approximately 2-fold increases in the number of BrdUrd-labeled cells, were observed at age 3 months, when neuronal loss and amyloid deposition are not detected. Because enhanced neurogenesis occurs in both AD and an animal model of AD, it seems to be caused by the disease itself and not by confounding clinical factors. As neurogenesis is increased in PDGF-APP(Sw,Ind) mice in the absence of neuronal loss, it must be triggered by more subtle disease manifestations, such as impaired neurotransmission. Enhanced neurogenesis in AD and animal models of AD suggests that neurogenesis may be a compensatory response and that measures to enhance neurogenesis further could have therapeutic potential.

Fig. 1.

Hippocampal histology in WT and PDGF-APP_Sw,Ind transgenic (Tg) mice. β-Amyloid immunohistochemistry (A) and cresyl violet staining of CA1 (B) show amyloid deposition in 1-year-old but not 3-month-old transgenic mice, and no CA1 neuronal loss at either age.

Fig. 2.

BrdUrd labeling of cells in DG-SGZ of 3-month-old (A and B) and 1-year-old (C and D) WT and PDGF-APP_Sw,Ind transgenic (Tg) mice. BrdUrd-labeled cells appear as black dots in A and C. The significance of differences between the number of BrdUrd-immunopositive cells in WT and transgenic mice in B and D was determined by Student's t test (n = 3-4).

Fig. 3.

BrdUrd labeling of cells in SVZ of 3-month-old (A and B) and 1-year-old (C and D) WT and PDGF-APP_Sw,Ind transgenic (Tg) mice. BrdUrd-labeled cells appear as black dots in A and C. The significance of differences between the number of BrdUrd-immunopositive cells in WT and transgenic mice in B and D was determined by Student's t test (n = 3-4).

Fig. 4.

Expression of immature neuronal marker proteins in DG-SGZ and SVZ of WT and PDGF-APP_Sw,Ind transgenic (Tg) mice. Sections through DG (A and B) and SVZ (C and D) of 3-month-old (A and C) and 1-year-old (B and D)WTand PDGF-APP_Sw,Ind transgenic mice were stained with an antibody against DCX (brown). Note that the number of DCX-immunoreactive cells in B (like the number of BrdUrd-labeled cells in Fig. 2D) was close to 0. Double-label immunohistochemistry with antibodies against BrdUrd and DCX (E) or BrdUrd and Neuro D (F) was performed on sections from 3-month-old transgenic mice and showed expression of DCX and Neuro D in BrdUrd-labeled cells in both DG-SGZ and SVZ.