| Alzheimer's disease (AD), the most common adult onset dementia, is aprogressive neurodegenerative disease associated with dysfunction and eventualdeath of brain neurons (Price, 1986). A pathologic hallmark of AD is theformation of senile plaques, in whichβ-amyloid peptide (Aβ) is a majorcomponent. Increased brain Aβlevels and/or Aβplaques may be the primaryinfluence resulting in neuronal degeneration in AD, and impaired long termpotentiation (LTP) in the hippocampus of AD model mice. The hippocampus isunique in continuing to produce new neurons throughout life in the structuresaffected by AD. Targeting neuronal regeneration (neurogenesis) in thehippocampus may be a potential therapy to delay or reverse the progression ofAD. However, because brain tissues from age-matched normal persons and ADpatients are generally not available, little is known about changes in endogenoushippocampal neurogenesis in the progression stage of AD. This study examinesthe changes in neurogenesis during the progression of AD with the goal ofidentifying a potential target for AD treatment. Transgenic mouse models of AD that carry an amyloid precursor protein(APP) and/or presenilinl (PS1) mutated gene show AD-like pathology andmemory impairment, and are useful for studying AD and testing possibletreatments. In this study, we used an APP/PS1 double transgenic mouse model ofAD to investigate changes in hippocampal neurogenesis through different stagesof AD. We tested the spatial memory of 3-and 9-month-old mice in a water mazeto determine the different stages of AD in the transgenic mice; the stage of ADwas confirmed by hippocampal Aβplaque staining. Hippocampal proliferatingcells in the mice were labeled by bromodeoxyuridine (BrdU) and doublecortin asmarkers for neuronal progenitor cells. To determine the differentiation ofproliferating cells, brain sections from mice injected with BrdU at 9 months andsacrificed at 10 months were double immunofluorescent labeled with antibodies,either BrdU + NeuN (a neuronal marker) or BrdU + glial fibrillary acidic protein(GFAP, an astroglia marker).Results as followed:1. Spatial memory acquisition of the mice was assessed by escape latency in thehidden-platform test in four blocks of training trials. Spatial memory retentionwas assessed in the probe test by the time spent (percentage) searching for thetarget quadrant. Memory was impaired in the 9-month-old transgenic mice in awater maze test.2. The number of hippocampal Aβplaques was used to confirm the differentstages of AD amyloid pathology in the different aged transgenic mice. Amyloidpathology was increased in the 9-month-old transgenic mice. The number ofhippocampal Aβplaques in the 9-month-old transgenic mice was significantlyhigher than in the 3-month old transgenic mice. No plaques were detected in thenontransgenic mice. 3. Cell proliferation in hippocampus of the mice was labeled by BrdU staining.In the 9-month-old mice, the number of BrdU-positive cells in the hippocampus,including dentate gyms (DG), CA1, and CA3 was significantly higher in thetransgenic mice than in the nontransgenic mice; these differences were notobserved in the 3-month-old mice.4. Cell proliferation in the hippocampus of 9-month-old mice was also labeledby DCX staining. The number of DCX-positive cells in the hippocampus,including DG, CA1, and CA3, was significantly higher in the transgenic micethan in the nontransgenic mice.5. To determine the relative distribution of phenotypes adopted by newproliferating cells in the hippocampus, mice were injeted with BrdU at 9 monthsand sacrificed 28 days after the last BrdU inj ection. The phenotypes of newproliferating cells in the DG, CA1, and CA3 regions include neuron (BrdU+NeuN double-positive cell) and glia (BrdU + GFAP double positive cell). Theproportion of differentiating BrdU-positive cells in transgenic and nontransgenicmice was similar, but the number of existing hippocampal BrdU-positive cellsand neurogenesis was higher in the transgenic mice.In summary, our findings are consistent with human postmortem brainstudies of AD patients that show increased hippocampal neurogenesis in DG andCA1. This study is the first to report on the changes of neurogenesis inAPPK670N/M671N/PS1M146L transgenic mice. As the APP/PS1 strain showsincreased neurogenesis in the progressive stage of AD, it may better reproducethe neurogenesis that is characteristic of AD patients. Although the function ofneurogenesis in the hippocampus of transgenic mice under physiological orpathological conditions is unknown, new neurons from the adult humanhippocampus have already shown some function. The formation of some types of memory relies on the continuous production of new hippocampal neuronsthroughout adulthood. Therefore, the increased neurogenesis in the ADtransgenic mice may be a compensatory response to pathological and behavioralimpairments Otherwise, new neuron may be not involved to neural network orshow some function. Although neurogenesis was increased in the hippocampus ofthe AD transgenic mouse model, the pathological change still worsened andmemory impairment could not be reversed over time. This may be due to theamount of increased neurogenesis not being sufficiently large to compensate forthe progressive pathological changes in the AD brain. Therefore, up-regulatingneurogenesis in the AD brain may be a potential therapeutic strategy for ADtreatment. |
