Recently it was demonstrated that exposure of the developing brain during the period of synaptogenesis to drugs that block NMDA glutamate receptors or drugs that potentiate GABA(A) receptors can trigger widespread apoptotic neurodegeneration. All currently used general anesthetic agents have either NMDA receptor-blocking or GABA(A) receptor-enhancing properties. To induce or maintain a surgical plane of anesthesia, it is common practice in pediatric or obstetrical medicine to use agents from these two classes in combination. Therefore, the question arises whether this practice entails significant risk of inducing apoptotic neurodegeneration in the developing human brain. To begin to address this problem, we have administered to 7-d-old infant rats a combination of drugs commonly used in pediatric anesthesia (midazolam, nitrous oxide, and isoflurane) in doses sufficient to maintain a surgical plane of anesthesia for 6 hr, and have observed that this causes widespread apoptotic neurodegeneration in the developing brain, deficits in hippocampal synaptic function, and persistent memory/learning impairments.

The deleterious effects of ethanol on the developing human brain are poorly understood. Here it is reported that ethanol, acting by a dual mechanism [blockade of N-methyl-D-aspartate (NMDA) glutamate receptors and excessive activation of GABA(A) receptors], triggers widespread apoptotic neurodegeneration in the developing rat forebrain. Vulnerability coincides with the period of synaptogenesis, which in humans extends from the sixth month of gestation to several years after birth. During this period, transient ethanol exposure can delete millions of neurons from the developing brain. This can explain the reduced brain mass and neurobehavioral disturbances associated with human fetal alcohol syndrome.

The gene encoding the transcriptional coactivator peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) was targeted in mice. PGC-1α null (PGC-1α−/−) mice were viable. However, extensive phenotyping revealed multi-system abnormalities indicative of an abnormal energy metabolic phenotype. The postnatal growth of heart and slow-twitch skeletal muscle, organs with high mitochondrial energy demands, is blunted in PGC-1α−/− mice. With age, the PGC-1α−/− mice develop abnormally increased body fat, a phenotype that is more severe in females. Mitochondrial number and respiratory capacity is diminished in slow-twitch skeletal muscle of PGC-1α−/− mice, leading to reduced muscle performance and exercise capacity. PGC-1α−/− mice exhibit a modest diminution in cardiac function related largely to abnormal control of heart rate. The PGC-1α−/− mice were unable to maintain core body temperature following exposure to cold, consistent with an altered thermogenic response. Following short-term starvation, PGC-1α−/− mice develop hepatic steatosis due to a combination of reduced mitochondrial respiratory capacity and an increased expression of lipogenic genes. Surprisingly, PGC-1α−/− mice were less susceptible to diet-induced insulin resistance than wild-type controls. Lastly, vacuolar lesions were detected in the central nervous system of PGC-1α−/− mice. These results demonstrate that PGC-1α is necessary for appropriate adaptation to the metabolic and physiologic stressors of postnatal life.

Apolipoprotein E (apoE) alleles determine the age-adjusted relative risk (4 > 3) for Alzheimer's disease (AD). ApoE may affect AD pathogenesis by promoting deposition of the amyloid-␤ (A␤) peptide and its conversion to a fibrillar form. To determine the effect of apoE on A␤ deposition and AD pathology, we compared APP V717F transgenic (TG) mice expressing mouse, human, or no apoE (apoE ؊͞؊ ). A severe, plaque-associated neuritic dystrophy developed in APP V717F TG mice expressing mouse or human apoE. Though significant levels of A␤ deposition also occurred in APP V717F TG, apoE ؊͞؊ mice, neuritic degeneration was virtually absent. Expression of apoE3 and apoE4 in APP V717F TG, apoE ؊͞؊ mice resulted in fibrillar A␤ deposits and neuritic plaques by 15 months of age and substantially (>10-fold) more fibrillar deposits were observed in apoE4-expressing APP V717F TG mice. Our data demonstrate a critical and isoform-specific role for apoE in neuritic plaque formation, a pathological hallmark of AD. M ultiple lines of evidence suggest that the deposition of amyloid-␤ (A␤) peptides is an early pathogenic event inAlzheimer's disease (AD) that initiates a cascade of changes ultimately resulting in neuronal dysfunction, neurodegeneration, and eventual death (1). Conversion of A␤ from a soluble to an aggregated, insoluble form(s) with a ␤-sheet conformation may be central to its accumulation and possibly for its detrimental effects (2). The formation of a prominent neuritic dystrophy (e.g., neuritic plaques) is likely to account for a significant amount of neuronal and accompanying cognitive dysfunction in AD (3). Whether, how, and what form of A␤ causes this prominent neuritic dystrophy is unclear. Understanding the pathogenesis of neuritic degeneration and its relationship to A␤ deposition and aggregation may allow for development of preventive treatments.Transgenic (TG) mice that develop age-and regiondependent A␤ deposition have provided a major advance in AD research (4, 5). These mice allow for the study of both disease pathogenesis and potential treatment strategies targeted at A␤ deposition and fibrillogenesis as well as their consequences such as neuritic degeneration (4-7). One protein that may play a role in A␤ deposition and neuritic degeneration is apolipoprotein E (apoE). We observed a severe, plaque-associated neuritic dystrophy in APP V717F TG mice with most fibrillar A␤ deposits surrounded by both large and fine dystrophic neurites. Importantly, we found that apoE is required for the extensive, plaqueassociated neuritic degeneration. In APP V717F TG, apoE Ϫ͞Ϫ mice, extensive, nonfibrillar A␤ deposits developed; however, A␤-associated neuritic degeneration almost never was observed. Astrocyte-specific expression of human apoE3 and E4 in APP V717F TG, apoE Ϫ͞Ϫ mice ultimately restored fibrillar A␤ deposition by 15 months of age, with expression of apoE4 having a markedly greater effect on neuritic plaque formation than apoE3. Our data strongly suggest a critical and isoform-specific role of apoE in influenci...

SUMMARY The mammalian Sir2 ortholog Sirt1 plays an important role in metabolic regulation. However, the role of Sirt1 in the regulation of aging and longevity is still controversial. Here we demonstrate that brain-specific Sirt1-overexpressing (BRASTO) transgenic mice show significant life span extension in both males and females, and aged BRASTO mice exhibit phenotypes consistent with a delay in aging. These phenotypes are mediated by enhanced neural activity specifically in the dorsomedial and lateral hypothalamic nuclei (DMH and LH, respectively), through increased orexin type 2 receptor (Ox2r) expression. We identified Nk2 homeobox 1 (Nkx2-1) as a novel partner of Sirt1 that upregulates Ox2r transcription and colocalizes with Sirt1 in the DMH and LH. DMH/LH-specific knockdown of Sirt1, Nkx2-1, or Ox2r and DMH-specific Sirt1 overexpression further support the role of Sirt1/Nkx2-1/Ox2r-mediated signaling for longevity-associated phenotypes. Our findings indicate the importance of DMH/LH-predominant Sirt1 activity in the regulation of aging and longevity in mammals.