1 September 2004. Before getting too excited about research findings in animals, AD researchers want to see similar data from human beings. An article in the September 7 issue of PNAS does the opposite, showing evidence of increased neurogenesis in an animal model of Alzheimer disease that supports results obtained from humans.
Late in 2003, David Greenberg, Kunlin Jin, and colleagues at Buck Institute for Aging in Novato, California, reported that they had found, in autopsy tissue of confirmed AD cases, increased expression of a number of immature neuron markers in the proliferative area of the hippocampus—the dentate gyrus's subgranular zone (DG-SGZ) (see ARF related news story).
First author Jin and colleagues now report on the birth of new neural cells in mice that carry both the Swedish (K595N/M596L) and Indiana (V717F) mutations that cause early-onset AD. The researchers counted newly born cells, as determined by BrdU labeling, in the DG-SGZ of three-month-old and one-year-old mice. At both ages, the transgenic mice had about twice the number of new cells as did wild-type littermates. In support of the case that these are new neurons, the researchers report finding them labeled with markers for the proteins doublecortin and Neuro D, both found in immature neurons.
By contrast, in the other brain area of adult neural proliferation, the subventricular zone, the researchers found increased BrdU labeling, as well as doublecortin and Neuro D, at one year of age, but not in the younger mice. The authors suggest that this difference may reflect the fact that the hippocampus is one of the areas where AD pathology first makes its appearance.
Jin and colleagues point out that their current study helps argue against some of the possible confounds in their study of human AD tissue. For example, the new findings militate against the possibility that nutritional deficiency—which occurs in late AD and which boosts neurogenesis in animals—might have led to increased neurogenesis. Similarly, cholinesterase inhibitors, memantine, statins, or nonsteroidal antiinflammatory drugs—all linked to increased neurogenesis and all potential confounds in human AD—were not present in the animals.
One question the results bring up is why increased neurogenesis would occur in three-month-old mice, where there is no evidence of the cell loss seen in older APPSw/Ind mice. The authors point out that this phenomenon has been described in an experimental model of epilepsy, and offer up the possibility that some other disease-associated pathology, such as defective neurotransmission, triggers neurogenesis.
The researchers are especially interested in defective neurotransmission because it may help explain why this study found increased hippocampal neurogenesis in AD transgenic mice, while other studies found impaired neurogenesis. The authors suggest that perhaps the addition of the Indiana (V717F) mutation made the difference. Describing one possible effect of the Indiana mutation on proliferation, Jin and colleagues note that by itself this mutation produces defects in synaptic transmission, and when combined with the Swedish mutation, it contributes to even larger synaptic defects (Hsia et al., 1999). Since hippocampal glutamatergic pathways are affected early in AD, and also in these double-transgenic mice, the authors suggest the possibility that, "a defect in glutamatergic transmission is what triggers neurogenesis in [APPSw,Ind] mice and patients with AD."—Hakon Heimer.
Jin K, Galvan B, Xie L, Mao XO, Gorostiza OF, Bredesen DE, Greenberg DA. Enhanced neurogenesis in Alzheimer's disease transgenic (PDGF-APPSw,Ind) mice. Proc Nat Acad Sci USA. 2004 September 7;101(36):13363-7. Abstract