BackgroundReduced TOR signaling has been shown to significantly increase lifespan in a variety of organisms [1], [2], [3], [4]. It was recently demonstrated that long-term treatment with rapamycin, an inhibitor of the mTOR pathway[5], or ablation of the mTOR target p70S6K[6] extends lifespan in mice, possibly by delaying aging. Whether inhibition of the mTOR pathway would delay or prevent age-associated disease such as AD remained to be determined.Methodology/Principal FindingsWe used rapamycin administration and behavioral tools in a mouse model of AD as well as standard biochemical and immunohistochemical measures in brain tissue to provide answers for this question. Here we show that long-term inhibition of mTOR by rapamycin prevented AD-like cognitive deficits and lowered levels of Aβ42, a major toxic species in AD[7], in the PDAPP transgenic mouse model. These data indicate that inhibition of the mTOR pathway can reduce Aβ42 levels in vivo and block or delay AD in mice. As expected from the inhibition of mTOR, autophagy was increased in neurons of rapamycin-treated transgenic, but not in non-transgenic, PDAPP mice, suggesting that the reduction in Aβ and the improvement in cognitive function are due in part to increased autophagy, possibly as a response to high levels of Aβ.Conclusions/SignificanceOur data suggest that inhibition of mTOR by rapamycin, an intervention that extends lifespan in mice, can slow or block AD progression in a transgenic mouse model of the disease. Rapamycin, already used in clinical settings, may be a potentially effective therapeutic agent for the treatment of AD.

CorrectionsAGRICULTURAL SCIENCES. For the article ''Characterization of capsaicin synthase and identification of its gene (csy1) for pungency factor capsaicin in pepper (Capsicum sp.),'' by B. C. Narasimha

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-APPSw,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 Ϸ2-fold increases in the number of BrdUrdlabeled 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-APPSw,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. N eurogenesis occurs in the adult brain and can be stimulated further by pathological processes, suggesting that newly generated neurons might be capable of replacing cells that are lost in neurological diseases. Animal models have been useful in identifying and characterizing injury-induced neurogenesis associated with epilepsy (1), ischemic stroke (2), and Parkinson's disease (3). Neurogenesis triggered by ischemia in rodents, for example, is associated with migration of newborn neurons from their sites of origin in the subventricular zone (SVZ) or dentate gyrus subgranular zone (DG-SGZ) into injured areas of the brain (4-6). Neurogenesis also generates functional neurons in adult human brain (7), and increased neurogenesis has been reported in patients with Huntington's disease (8) and Alzheimer's disease (AD) (9). These findings are encouraging with respect to prospects for cell-replacement therapy because the persistent stimulus-responsiveness of neurogenesis in neurodegenerative diseases indicates that additional stimulation and regulation by therapeutic interventions may be possible.Recently, we found that neurogenesis is increased in the DG-SGZ from patients with AD (9). Compared to controls, AD brains showed increased expression of the immature neuronal markers doublecortin (DCX), embryonic nerve cell adhesion molecule, neurogenic differentiation factor Neuro D, and turned-on-after-division͞Ulip-1͞CRMP-4. Expression of DCX and turned-on-after-division͞Ulip-1͞CRMP-4 was associated with neurons in DG-SGZ, the DG granule cell layer, which is the physiological destination of these neurons, and the CA1 region of Ammon's horn, which is the principal site of hippocampal pathology in AD. These findings suggest that neurogenesis is increased in AD hippocampus, where it ...

Transplantation of neural cells is a potential approach for the treatment of stroke, but the disruption of tissue architecture that accompanies stroke may limit the efficacy of transplantation. One strategy for enhancing the ability of transplants to restore brain structure and, thereby, function is to administer cells together with biomaterial scaffolding. We occluded the middle cerebral artery in adult rats and, 3 wks later, injected one of the following into the infarct cavity: (a) artificial cerebrospinal fluid, (b) Matrigel scaffolding, (c) human neuronal precursor cells, (d) scaffolding plus cells, or (e) cells cultured in and administered together with scaffolding. When tested up to 9 wks later, the latter group showed reduced infarct size, survival and neuronal differentiation of transplanted cells, and improved outcome on behavioral tests of sensorimotor and cognitive function. These results indicate that transplantation of human neural cells together with the scaffolding in which they are cultured has the potential to improve outcome from stroke, even when treatment is delayed for several weeks after the ischemic event.

Numerous studies have demonstrated oxidative damage in the central nervous system in subjects with Alzheimer disease and in animal models of this dementing disorder. In the current study, we show that transgenic mice modeling Alzheimer disease-PDAPP mice with Swedish and Indiana mutations in human amyloid precursor protein (APP)-develop oxidative damage in brain, including elevated levels of protein oxidation (indexed by protein carbonyls and 3-nitrotyrosine) and lipid peroxidation (indexed by protein-bound 4-hydroxy-2-nonenal). This oxidative damage requires the presence of a single methionine residue at position 35 of the amyloid β-peptide (Aβ), since all indices of oxidative damage in brain were completely prevented in genetically and age-matched PDAPP mice with a M631L mutation in APP. No significant differences in levels of APP, Aβ(1-42), Aβ (1-40), or the ratio Aβ(1-42)/Aβ(1-40) were found, suggesting that the loss of oxidative stress in vivo in brain of PDAPP(M631L) mice results solely from the mutation of the Met35 residue to Leu in the Aβ peptide. However, a marked reduction in Aβ-immunoreactive plaques was observed in the M631L mice, which instead displayed small punctate areas of non-plaque immunoreactivity and a microglial response. In contrast to the requirement for Met at residue 35 of the Aβ sequence (M631 of APP) for oxidative damage, indices of spatial learning and memory were not significantly improved by the M631L substitution. Furthermore, a genetically matched line with a different mutation-PDAPP(D664A)-showed the reverse: no reduction in oxidative damage but marked improvement in memory. This is the first in vivo study to demonstrate the requirement for Aβ residue Met35 for oxidative stress in brain of a mammalian model of Alzheimer disease. However, in this specific transgenic mouse model of AD, oxidative stress is neither required nor sufficient for memory abnormalities.