Alzheimer’s disease (AD) is a progressive, neurodegenerative disease characterized by progressive decline of memory and cognitive functions. Despite tremendous progress that has been made in understanding disease progression and therapeutics of AD, we still do not have drugs that are capable of slowing its progression. The purpose of our study was to investigate the effects of the mitochondria-targeted antioxidants (MTAs) MitoQ and SS31, and the anti-aging agent resveratrol on neurons from a mouse model of Alzheimer’s disease (AD) (Tg2576 line) and on mouse neuroblastoma (N2a) cells incubated with the amyloid beta (Aβ) peptide. Using electron and confocal microscopy, gene expression analysis, and biochemical methods, we studied mitochondrial structure and function, and neurite outgrowth in N2a cells treated with MitoQ, SS31, and resveratrol, and then incubated with Aβ. In N2a cells only incubated with the Aβ, we found increased expressions of mitochondrial fission genes and decreased expression of fusion genes, and also decreased expression of peroxiredoxins, endogenous cytoprotective antioxidant enzymes. Electron microscopy of the N2a cells incubated with Aβ revealed a significantly increased number of mitochondria, indicating that Aβ fragments mitochondria. Biochemical analysis revealed that function is defective in mitochondria. Neurite outgrowth was significantly decreased in Aβ-incubated N2a cells, indicating that Aβ affects neurite outgrowth. However, in N2a cells treated with MitoQ, SS31, and resveratrol, and then incubated with Aβ, abnormal expression of peroxiredoxins and mitochondrial structural genes were prevented and mitochondrial function was normal; intact mitochondria were present and neurite outgrowth was significantly increased. In primary neurons from amyloid beta precursor protein (AβPP) transgenic mice that were treated with MitoQ and SS31, neurite outgrowth was significantly increased and cyclophilin D expression was significantly decreased. These findings suggest that the MTAs, MitoQ and SS31 prevent Aβ toxicity in mitochondria, which would warrant the study of MitoQ and SS31 as potential drugs to treat patients with AD.

As neurons of the developing brain form functional circuits, they undergo morphological differentiation. In immature cerebral cortex, radially-oriented cellular processes of undifferentiated neurons impede water diffusion parallel, but not perpendicular, to the pial surface, as measured via diffusion-weighted magnetic resonance imaging, and give rise to water diffusion anisotropy. As the cerebral cortex matures, the loss of water diffusion anisotropy accompanies cellular morphological differentiation. A quantitative relationship is proposed here to relate water diffusion anisotropy measurements directly to characteristics of neuronal morphology. This expression incorporates the effects of local diffusion anisotropy within cellular processes, as well as the effects of anisotropy in the orientations of cellular processes. To obtain experimental support for the proposed relationship, tissue from 13 and 31 day-old ferrets was stained using the rapid Golgi technique, and the 3-D orientation distribution of neuronal proceses was characterized using confocal microscopic examination of reflected visible light images. Coregistration of the MRI and Golgi data enables a quantitative evaluation of the proposed theory, and excellent agreement with the theoretical results, as well as agreement with previously published values for locally-induced water diffusion anisotropy and volume fraction of the neuropil, is observed.

Activation of erbB-1 receptors by glial TGFalpha has been shown to be a component of the developmental program by which the neuroendocrine brain controls mammalian sexual development. The participation of other members of the erbB family may be required, however, for full signaling capacity. Here, we show that activation of astrocytic erbB-2/erbB-4 receptors plays a significant role in the process by which the hypothalamus controls the advent of mammalian sexual maturation. Hypothalamic astrocytes express both the erbB-2 and erbB-4 genes, but no erbB-3, and respond to neuregulins (NRGs) by releasing prostaglandin E(2) (PGE(2)), which acts on neurosecretory neurons to stimulate secretion of luteinizing hormone-releasing hormone (LHRH), the neuropeptide controlling sexual development. The actions of TGFalpha and NRGs in glia are synergistic and involve recruitment of erbB-2 as a coreceptor, via erbB-1 and erbB-4, respectively. Hypothalamic expression of both erbB-2 and erbB-4 increases first in a gonad-independent manner before the onset of puberty, and then, at the time of puberty, in a sex steroid-dependent manner. Disruption of erbB-2 synthesis in hypothalamic astrocytes by treatment with an antisense oligodeoxynucleotide inhibited the astrocytic response to NRGs and, to a lesser extent, that to TGFalpha and blocked the erbB-dependent, glia-mediated, stimulation of LHRH release. Intracerebral administration of the oligodeoxynucleotide to developing animals delayed the initiation of puberty. Thus, activation of the erbB-2-erbB-4 receptor complex appears to be a critical component of the signaling process by which astrocytes facilitate the acquisition of female reproductive capacity in mammals.

The activation of transforming growth factor ␣ (TGF␣)-erbB-1 and neuregulin-erbB-4 signaling pathways in hypothalamic astrocytes has been shown to play a key role in the process by which the neuroendocrine brain controls luteinizing hormone-releasing hormone (LHRH) secretion. Earlier studies suggested that tanycytes, an ependymoglial cell type of the median eminence, regulate LHRH release during the estrous cycle by undergoing plastic changes that alternatively allow or prevent direct access of the LHRH nerve terminals to the portal vasculature. Neither the molecules responsible for these plastic changes nor the underlying controlling mechanisms have been identified. Here we show that cultured tanycytes express erbB-1 and erbB-2, two of the four members of the erbB receptor family, and respond to TGF␣ with receptor phosphorylation, release of prostaglandin E 2 (PGE 2 ), and a PGE 2 -dependent increase in the release of TGF␤ 1 , a growth factor previously implicated in the glial control of LHRH secretion. Blockade of either erbB-1 receptor signal transduction or prostaglandin synthesis prevented the stimulatory effect of TGF␣ on both PGE 2 and TGF␤ 1 release. Time-lapse studies revealed that TGF␣ and TGF␤ 1 have dramatically opposite effects on tanycyte plasticity. Whereas TGF␣ promotes tanycytic outgrowth, TGF␤ 1 elicits retraction of tanycytic processes. Blockade of metalloproteinase activity abolished the effect of TGF␤ 1 , suggesting that TGF␤ 1 induces tanycytic retraction by facilitating dissolution of the extracellular matrix. Prolonged (Ͼ12 hr) exposure of tanycytes to TGF␣ resulted in focal tanycytic retraction, an effect that was abolished by immunoneutralization of TGF␤ 1 action, indicating that the retraction was attributable to TGF␣-induced TGF␤ 1 formation. These in vitro results identify tanycytes as targets of TGF␣ action and demonstrate that activation of erbB-1-mediated signaling in these cells results in plastic changes that, involving PGE 2 and TGF␤ 1 as downstream effectors, mimic the morphological plasticity displayed by tanycytes during the hours encompassing the preovulatory surge of LHRH.