Limited hippocampal neurogenesis in SAMP8 mouse model of Alzheimer's disease

Increasing adult neurogenesis in the hippocampal formation (HF) has been proposed as a potential foundation for neuronal repair in Alzheimer's disease (AD), but the evidence remains controversial. We used P8 strain of senescence-accelerated mice (SAMP8) as a model of AD to investigate changes in adult neurogenesis. We examined new proliferating cells and their survival in the dentate gyrus (DG) of the HF using 5-bromodeoxyuridine (BrdU) labeling and investigated newborn cell development and differentiation with a combination of phenotype markers. In 5-month-old SAMP8, the number of BrdU+ cells in the DG was significantly increased relative to controls, in accordance with the rising numbers of doublecortin-positive (DCX+) immature neurons. Some of these BrdU+ cells migrated to cornu ammonis 1 (CA1), possibly related to the compensation of neuronal loss. However, the capacity of neurogenesis to compensate neuronal loss during neurodegeneration was limited. First, only half of the BrdU+ cells survived 4 weeks after mitosis, and even fewer developed into neuron-specific nuclear protein positive (NeuN+) mature neurons. Second, the number of BrdU+ cells and DCX+ cells was decreased in 10-month-old SAMP8, which exhibited progressive neurodegeneration. In addition, the results provided insight into astrocytes as a crucial component of the neurogenic niche. The number of newborn astrocytes and expression of glial fibrillary acidic protein (GFAP) were diminished in the DG of SAMP8 animals, possibly explaining the insufficient neurogenesis. Thus, stimulating limited neurogenesis in AD by improving the neurogenic niche may have therapeutic potential.

Research highlights
► The SAMP8 was used as a model of Alzheimer's disease (AD).
► The SAMP8 had enhanced hippocampal adult neurogenesis (HAN).
► Enhanced HAN was insufficient to reverse the neuron loss in SAMP8.
► The HAN was reduced with the developing age of SAMP8.
► The changes of hippocampal astroglia may be related to this limited neurogenesis.