The role of estrogens in Alzheimer's disease (AD) involving β-amyloid (Aβ) generation and plaque formation was mostly tested in ovariectomized mice with or without APP mutations. The aim of the present study was to explore the abnormalities of neural cells in a novel mouse model of AD with chronic estrogen deficiency. These chimeric mice exhibit a total FSH-R knockout (FORKO) and carry two transgenes, one expressing the β-amyloid precursor protein (APPsw, Swedish mutation) and the other expressing presenilin-1 lacking exon 9 (PS1Δ9). The most prominent changes in the cerebral cortex and hippocampus of these hypoestrogenic mice were marked hypertrophy of both cortical neurons and astrocytes and an increased number of activated microglia. There were no significant differences in the number of Aβ plaques although they appeared less compacted and larger than those in APPsw/PS1Δ9 control mice. Similar glia abnormalities were obtained in wild-type primary cortical neural cultures treated with letrozole, an aromatase inhibitor. The concordance of results from APPsw/PS1Δ9 mice with or without FSH-R deletion and those with letrozole treatment in vitro (with and without Aβ treatment) of primary cortical/hippocampal cultures suggests the usefulness of these models to explore molecular mechanisms involved in microglia and astrocyte activation in hypoestrogenic states in the central nervous system. 1. Introduction In the brain, estradiol is formed in neurons and a subpopulation of astrocytes by aromatase-mediated conversion of precursor androgens [1]. Estrogen deficiency was reported to accelerate β-amyloid (Aβ) plaque formation in an Alzheimer’s disease (AD) mouse model combining an aromatase deficiency and an APP23 transgene [2]. There was no significant difference between the estrogen levels in APP23 and wild-type mice independent of age (3, 6, and 12 months); however, the estrogen levels in the brains of APP23-aromatase knockout mice were significantly reduced compared to age-matched ovariectomized APP23 mice. Furthermore, microglial cultures prepared from the brains of these APP23 mice showed impaired Aβ clearance and/or degradation [2]. Another model of estrogen imbalance was provided by follicule-stimulating hormone receptor (FSHR) knockout (FORKO) mice [3]. Our earlier studies showed that homozygous females were infertile, whereas males exhibited reduced fertility [4]. Similarly, inactivating mutations in the FSHR gene in women cause absolute infertility and amenorrhea [5]. Young and aged FORKO mice exhibit several biochemical and morphological abnormalities
References
[1]
I. Azcoitia, J. G. Yague, and L. M. Garcia-Segura, “Estradiol synthesis within the human brain,” Neuroscience, vol. 191, pp. 139–147, 2011.
[2]
X. Yue, M. Lu, T. Lancaster et al., “Brain estrogen deficiency accelerates Aβ plaque formation in an Alzheimer's disease animal model,” Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 52, pp. 19198–19203, 2005.
[3]
A. Dierich, M. R. Sairam, L. Monaco et al., “Impairing follicle-stimulating hormone (FSH) signaling in vivo: targeted disruption of the FSH receptor leads to aberrant gametogenesis and hormonal imbalance,” Proceedings of the National Academy of Sciences of the United States of America, vol. 95, no. 23, pp. 13612–13617, 1998.
[4]
H. Krishnamurthy, R. Kats, N. Danilovich, D. Javeshghani, and M. R. Sairam, “Intercellular communication between Sertoli cells and Leydig cells in the absence of follicle-stimulating hormone-receptor signaling,” Biology of Reproduction, vol. 65, no. 4, pp. 1201–1207, 2001.
[5]
C. H. Matthews, S. Borgato, P. Beck-Peccoz et al., “Primary amenorrhoea and infertility due to a mutation in the β-subunit of follicle-stimulating hormone,” Nature Genetics, vol. 5, no. 1, pp. 83–86, 1993.
[6]
J. Tam, N. Danilovich, K. Nilsson, M. R. Sairam, and D. Maysinger, “Chronic estrogen deficiency leads to molecular aberrations related to neurodegenerative changes in follitropin receptor knockout female mice,” Neuroscience, vol. 114, no. 2, pp. 493–506, 2002.
[7]
N. Danilovich, M. R. Sairam, and D. Maysinger, “The menopausal mouse: a new neural paradigm of a distressing human condition,” NeuroReport, vol. 14, no. 12, pp. 1617–1622, 2003.
[8]
L. Rumora, J. Lovri？, M. R. Sairam, and D. Maysinger, “Impairments of heat shock protein expression and MAPK translocation in the central nervous system of follitropin receptor knockout mice,” Experimental Gerontology, vol. 42, no. 7, pp. 619–628, 2007.
[9]
M. R. Sairam, M. Wang, N. Danilovich, D. Javeshghani, and D. Maysinger, “Early obesity and age-related mimicry of metabolic syndrome in female mice with sex hormonal imbalances,” Obesity, vol. 14, no. 7, pp. 1142–1154, 2006.
[10]
N. Danilovich, D. Maysinger, and M. R. Sairam, “Perspectives on reproductive senescence and biological aging: studies in genetically altered follitropin receptor knockout [FORKO] mice,” Experimental Gerontology, vol. 39, no. 11-12, pp. 1669–1678, 2004.
[11]
D. Javeshghani, E. L. Schiffrin, M. R. Sairam, and R. M. Touyz, “Potentiation of vascular oxidative stress and nitric oxide-mediated endothelial dysfunction by high-fat diet in a mouse model of estrogen deficiency and hyperandrogenemia,” Journal of the American Society of Hypertension, vol. 3, no. 5, pp. 295–305, 2009.
[12]
N. R. Bhat, “Linking cardiometabolic disorders to sporadic Alzheimer's disease: a perspective on potential mechanisms and mediators,” Journal of Neurochemistry, vol. 115, no. 3, pp. 551–562, 2010.
[13]
T. C. de Toledo Ferraz Alves, L. K. Ferreira, M. Wajngarten, and G. F. Busatto, “Cardiac disorders as risk factors for Alzheimer's disease,” Journal of Alzheimer's Disease, vol. 20, no. 3, pp. 749–763, 2010.
[14]
E. Hogervorst and S. Bandelow, “The controversy over levels of sex steroids in cases with Alzheimer's disease,” Journal of Neuroendocrinology, vol. 16, no. 2, pp. 93–94, 2004.
[15]
C. E. Gleason, B. Cholerton, C. M. Carlsson, S. C. Johnson, and S. Asthana, “Neuroprotective effects of female sex steroids in humans: current controversies and future directions,” Cellular and Molecular Life Sciences, vol. 62, no. 3, pp. 299–312, 2005.
[16]
G. M. Rune, C. Lohse, J. Prange-Kiel, L. Fester, and M. Frotscher, “Synaptic plasticity in the hippocampus: effects of estrogen from the gonads or hippocampus?” Neurochemical Research, vol. 31, no. 2, pp. 145–155, 2006.
[17]
S. C. Correia, R. X. Santos, S. Cardoso et al., “Effects of estrogen in the brain: is it a neuroprotective agent in alzheimer's disease?” Current Aging Science, vol. 3, no. 2, pp. 113–126, 2010.
[18]
E. S. Leblanc, J. Janowsky, B. K. S. Chan, and H. D. Nelson, “Hormone replacement therapy and cognition: systematic review and meta-analysis,” JAMA, vol. 285, no. 11, pp. 1489–1499, 2001.
[19]
H. Allain, D. Bentué-Ferrer, and Y. Akwa, “Treatment of the mild cognitive impairment (MCI),” Human Psychopharmacology, vol. 22, no. 4, pp. 189–197, 2007.
[20]
V. W. Henderson, “Action of estrogens in the aging brain: dementia and cognitive aging,” Biochimica et Biophysica Acta, vol. 1800, no. 10, pp. 1077–1083, 2010.
[21]
C. Behl, “Oestrogen as a neuroprotective hormone,” Nature Reviews Neuroscience, vol. 3, no. 6, pp. 433–442, 2002.
[22]
E. Vegeto, V. Benedusi, and A. Maggi, “Estrogen anti-inflammatory activity in brain: a therapeutic opportunity for menopause and neurodegenerative diseases,” Frontiers in Neuroendocrinology, vol. 29, no. 4, pp. 507–519, 2008.
[23]
K. M. Dhandapani and D. W. Brann, “Role of astrocytes in estrogen-mediated neuroprotection,” Experimental Gerontology, vol. 42, no. 1-2, pp. 70–75, 2007.
[24]
A. Sierra, A. Gottfried-Blackmore, T. A. Milner, B. S. McEwen, and K. Bulloch, “Steroid hormone receptor expression and function in microglia,” Glia, vol. 56, no. 6, pp. 659–674, 2008.
[25]
A. Nimmerjahn, F. Kirchhoff, and F. Helmchen, “Neuroscience: resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo,” Science, vol. 308, no. 5726, pp. 1314–1318, 2005.
[26]
A. R. Simard and S. Rivest, “Neuroprotective effects of resident microglia following acute brain injury,” Journal of Comparative Neurology, vol. 504, no. 6, pp. 716–729, 2007.
[27]
M. B. Graeber, “Changing face of microglia,” Science, vol. 330, no. 6005, pp. 783–788, 2010.
[28]
M. L. Block, L. Zecca, and J. S. Hong, “Microglia-mediated neurotoxicity: uncovering the molecular mechanisms,” Nature Reviews Neuroscience, vol. 8, no. 1, pp. 57–69, 2007.
[29]
M. L. Block, “NADPH oxidase as a therapeutic target in Alzheimer's disease,” BMC Neuroscience, vol. 9, supplement 2, article S8, 2008.
[30]
M. E. Lull and M. L. Block, “Microglial activation and chronic neurodegeneration,” Neurotherapeutics, vol. 7, no. 4, pp. 354–365, 2010.
[31]
E. G. McGeer and P. L. McGeer, “Neuroinflammation in Alzheimer's disease and mild cognitive impairment: a field in its infancy,” Journal of Alzheimer's Disease, vol. 19, no. 1, pp. 355–361, 2010.
[32]
G. Candore, C. R. Balistreri, M. P. Grimaldi et al., “Age-related inflammatory diseases: role of genetics and gender in the pathophysiology of Alzheimer's disease,” Annals of the New York Academy of Sciences, vol. 1089, pp. 472–486, 2006.
[33]
P. Agostinho, R. A. Cunha, and C. Oliveira, “Neuroinflammation, oxidative stress and the pathogenesis of Alzheimer's disease,” Current Pharmaceutical Design, vol. 16, no. 25, pp. 2766–2778, 2010.
[34]
P. L. McGeer, M. Schulzer, and E. G. McGeer, “Arthritis and anti-inflammatory agents as possible protective factors for Alzheimer's disease: a review of 17 epidemiologic studies,” Neurology, vol. 47, no. 2, pp. 425–432, 1996.
[35]
P. L. McGeer and E. G. McGeer, “NSAIDs and Alzheimer disease: epidemiological, animal model and clinical studies,” Neurobiology of Aging, vol. 28, no. 5, pp. 639–647, 2007.
[36]
D. G. Walker and L. F. Lue, “Investigations with cultured human microglia on pathogenic mechanisms of Alzheimer's disease and other neurodegenerative diseases,” Journal of Neuroscience Research, vol. 81, no. 3, pp. 412–425, 2005.
[37]
S. Mandrekar, Q. Jiang, C. Y. D. Lee, J. Koenigsknecht-Talboo, D. M. Holtzman, and G. E. Landreth, “Microglia mediate the clearance of soluble aβ through fluid phase macropinocytosis,” Journal of Neuroscience, vol. 29, no. 13, pp. 4252–4262, 2009.
[38]
J. G？tz and L. M. Ittner, “Animal models of Alzheimer's disease and frontotemporal dementia,” Nature Reviews Neuroscience, vol. 9, no. 7, pp. 532–544, 2008.
[39]
D. R. Borchelt, G. Thinakaran, C. B. Eckman et al., “Familial Alzheimer's disease-linked presenilin I variants elevate aβ1- 42/1-40 ratio in vitro and in vivo,” Neuron, vol. 17, no. 5, pp. 1005–1013, 1996.
[40]
D. R. Borchelt, T. Ratovitski, J. van Lare et al., “Accelerated amyloid deposition in the brains of transgenic mice coexpressing mutant presenilin 1 and amyloid precursor proteins,” Neuron, vol. 19, no. 4, pp. 939–945, 1997.
[41]
G. Thinakaran, D. R. Borchelt, M. K. Lee et al., “Endoproteolysis of presenilin 1 and accumulation of processed derivatives in vivo,” Neuron, vol. 17, no. 1, pp. 181–190, 1996.
[42]
K. F. Bell, G. J. de Kort, S. Steggerda, R. Shigemoto, A. Ribeiro-da-Silva, and A. C. Cuello, “Structural involvement of the glutamatergic presynaptic boutons in a transgenic mouse model expressing early onset amyloid pathology,” Neuroscience Letters, vol. 353, no. 2, pp. 143–147, 2003.
[43]
K. F. Bell, A. Ducatenzeiler, A. Ribeiro-da-Silva, K. Duff, D. A. Bennett, and A. C. Cuello, “The amyloid pathology progresses in a neurotransmitter-specific manner,” Neurobiology of Aging, vol. 27, no. 11, pp. 1644–1657, 2006.
[44]
P. M. Wise, “Neuroendocrine modulation of the “menopause”: insights into the aging brain,” American Journal of Physiology, vol. 277, no. 6, pp. E965–E970, 1999.
[45]
H. Barelli, A. Lebeau, J. Vizzavona et al., “Characterization of new polyclonal antibodies specific for 40 and 42 amino acid-long amyloid β peptides: their use to examine the cell biology of presenilins and the immunohistochemistry of sporadic Alzheimer's disease and cerebral amyloid angiopathy cases,” Molecular Medicine, vol. 3, no. 10, pp. 695–707, 1997.
[46]
R. G. Cutler, J. Kelly, K. Storie et al., “Involvement of oxidative stress-induced abnormalities in ceramide and cholesterol metabolism in brain aging and Alzheimer's disease,” Proceedings of the National Academy of Sciences of the United States of America, vol. 101, no. 7, pp. 2070–2075, 2004.
[47]
I. L. Ferreira, R. Resende, E. Ferreiro, A. C. Rego, and C. F. Pereira, “Multiple defects in energy metabolism in Alzheimer's disease,” Current Drug Targets, vol. 11, no. 10, pp. 1193–1206, 2010.
[48]
H. Du, L. Guo, S. Yan, A. A. Sosunov, G. M. McKhann, and S. S. Yan, “Early deficits in synaptic mitochondria in an Alzheimer's disease mouse model,” Proceedings of the National Academy of Sciences of the United States of America, vol. 107, no. 43, pp. 18670–18675, 2010.
[49]
J. W. Simpkins, K. D. Yi, S. H. Yang, and J. A. Dykens, “Mitochondrial mechanisms of estrogen neuroprotection,” Biochimica et Biophysica Acta, vol. 1800, no. 10, pp. 1113–1120, 2010.
[50]
H.-L. Wang, A.-H. Chou, A.-S. Wu et al., “PARK6 PINK1 mutants are defective in maintaining mitochondrial membrane potential and inhibiting ROS formation of substantia nigra dopaminergic neurons,” Biochimica et Biophysica Acta, vol. 1812, no. 6, pp. 674–684, 2011.
[51]
D. Manthey and C. Behl, “From structural biochemistry to expression profiling: neuroprotective activities of estrogen,” Neuroscience, vol. 138, no. 3, pp. 845–850, 2006.
[52]
T. Smejkalova and C. S. Woolley, “Estradiol acutely potentiates hippocampal excitatory synaptic transmission through a presynaptic mechanism,” Journal of Neuroscience, vol. 30, no. 48, pp. 16137–16148, 2010.
[53]
J. L. Herrera, C. Fernandez, M. Diaz, D. Cury, and R. Marin, “Estradiol and tamoxifen differentially regulate a plasmalemmal voltage-dependent anion channel involved in amyloid-beta induced neurotoxicity,” Steroids, vol. 76, no. 9, pp. 840–844, 2011.
[54]
K. F. Manaye, J. S. Allard, S. Kalifa, et al., “17alpha-estradiol attenuates neuron lossin ovariectomized Dtg AbetaPP/PS1 mice,” Journal of Alzheimer's Disease, vol. 23, no. 4, pp. 629–639, 2011.
[55]
A. Morinaga, K. Ono, J. Takasaki, T. Ikeda, M. Hirohata, and M. Yamada, “Effects of sex hormones on Alzheimer's disease-associated β-amyloid oligomer formation in vitro,” Experimental Neurology, vol. 228, no. 2, pp. 298–302, 2011.
[56]
B. B. Sherwin, “Estrogen and cognitive aging in women,” Trends in Pharmacological Sciences, vol. 23, no. 11, pp. 527–534, 2002.
[57]
R. D. Brinton, “Requirements of a brain selective estrogen: advances and remaining challenges for developing a NeuroSERM,” Journal of Alzheimer's Disease, vol. 6, pp. S27–S35, 2004.
[58]
M. C. Craig, P. M. Maki, and D. G. M. Murphy, “The Women's health initiative memory study: findings and implications for treatment,” The Lancet Neurology, vol. 4, no. 3, pp. 190–194, 2005.
[59]
M. A. Arevalo, M. Santos-Galindo, M. J. Bellini, I. Azcoitia, and L. M. Garcia-Segura, “Actions of estrogens on glial cells: implications for neuroprotection,” Biochimica et Biophysica Acta, vol. 1800, no. 10, pp. 1106–1112, 2010.
[60]
J. A. Smith, A. Das, J. T. Butler, S. K. Ray, and N. L. Banik, “Estrogen or estrogen receptor agonist inhibits lipopolysaccharide induced microglial activation and death,” Neurochemical Research, vol. 36, no. 9, pp. 1587–1593, 2011.
[61]
U. K. Hanisch and H. Kettenmann, “Microglia: active sensor and versatile effector cells in the normal and pathologic brain,” Nature Neuroscience, vol. 10, no. 11, pp. 1387–1394, 2007.
[62]
E. R. te Velde, G. J. Scheffer, M. Dorland, F. J. Broekmans, and B. C. J. M. Fauser, “Developmental and endocrine aspects of normal ovarian aging,” Molecular and Cellular Endocrinology, vol. 145, no. 1-2, pp. 67–73, 1998.
[63]
F. L. Bellino, “Nonprimate animal models of menopause: workshop report,” Menopause, vol. 7, no. 1, pp. 14–24, 2000.
[64]
E. E. Baulieu, “On ‘steroid aging’,” Comptes Rendus Biologies, vol. 325, no. 6, pp. 747–749, 2002.
[65]
A. Novák, M. Brod, and J. Elbers, “Andropause and quality of life: findings from patient focus groups and clinical experts,” Maturitas, vol. 43, no. 4, pp. 231–237, 2002.
[66]
N. B. Huri, “X-Rays, a vital tool, but use it carefully,” Dental Student, vol. 53, no. 9, article 60,70, 1975.
[67]
J. Stepan, J. Pospichal, J. Formankova, et al., “Transdermal estradiol in the prevention of the menopause-induced increase in osteoresorption,” Ceskoslovenská Gynekologie, vol. 54, no. 7, pp. 496–505, 1989.
[68]
V. A. Giagulli, J. M. Kaufman, and A. Vermeulen, “Pathogenesis of the decreased androgen levels in obese men,” Journal of Clinical Endocrinology and Metabolism, vol. 79, no. 4, pp. 997–1000, 1994.
[69]
S. Nolen-Hoeksema, “The role of rumination in depressive disorders and mixed anxiety/depressive symptoms,” Journal of Abnormal Psychology, vol. 109, no. 3, pp. 504–511, 2000.
[70]
R. L. Roof and E. D. Hall, “Estrogen-related gender difference in survival rate and cortical blood flow after impact-acceleration head injury in rats,” Journal of Neurotrauma, vol. 17, no. 12, pp. 1155–1169, 2000.
[71]
Y. Takahashi, H. Hohjoh, and K. Matsuura, “Predisposing factors in delayed sleep phase syndrome,” Psychiatry and Clinical Neurosciences, vol. 54, no. 3, pp. 356–358, 2000.
[72]
B. S. McEwen, “Estrogens effects on the brain: multiple sites and molecular mechanisms,” Journal of Applied Physiology, vol. 91, no. 6, pp. 2785–2801, 2001.
[73]
R. S. Tan and S. J. Pu, “Impact of obesity on hypogonadism in the andropause,” International Journal of Andrology, vol. 25, no. 4, pp. 195–201, 2002.
[74]
A. von Eckardstein and F. C. W. Wu, “Testosterone and atherosclerosis,” Growth Hormone and IGF Research, vol. 13, pp. S72–S84, 2003.
[75]
M. Oettel, D. Hübler, and V. Patchev, “Selected aspects of endocrine pharmacology of the aging male,” Experimental Gerontology, vol. 38, no. 1-2, pp. 189–198, 2003.
[76]
R. S. Swerdloff and C. Wang, “Androgens and the ageing male,” Best Practice and Research: Clinical Endocrinology and Metabolism, vol. 18, no. 3, pp. 349–362, 2004.
[77]
C. von Schassen, L. Fester, J. Prange-Kiel et al., “Oestrogen synthesis in the hippocampus: role in axon outgrowth,” Journal of Neuroendocrinology, vol. 18, no. 11, pp. 847–856, 2006.
[78]
L. Zhou, L. Fester, B. von Blittersdorff et al., “Aromatase inhibitors induce spine synapse loss in the hippocampus of ovariectomized mice,” Endocrinology, vol. 151, no. 3, pp. 1153–1160, 2010.
[79]
I. Azcoitia, M. Santos-Galindo, M. A. Arevalo, and L. M. Garcia-Segura, “Role of astroglia in the neuroplastic and neuroprotective actions of estradiol,” European Journal of Neuroscience, vol. 32, no. 12, pp. 1995–2002, 2010.
[80]
M. A. Arevalo, Y. Diz-Chaves, M. Santos-Galindo, M. J. Bellini, and L. M. Garcia-Segura, “Selective oestrogen receptor modulators decrease the inflammatory response of Glial cells,” Journal of Neuroendocrinology, 2011.
[81]
M. Tenenbaum, A. N. Azab, and J. Kaplanski, “Effects of estrogen against LPS-induced inflammation and toxicity in primary rat glial and neuronal cultures,” Journal of Endotoxin Research, vol. 13, no. 3, pp. 158–166, 2007.
[82]
M. Cerciat, M. Unkila, L. M. Garcia-Segura, and M. A. Arevalo, “Selective estrogen receptor modulators decrease the production of interleukin-6 and interferon-γ-inducible protein-10 by astrocytes exposed to inflammatory challenge in vitro,” Glia, vol. 58, no. 1, pp. 93–102, 2010.
[83]
D. C. Hess, T. Abe, W. D. Hill et al., “Hematopoietic origin of microglial and perivascular cells in brain,” Experimental Neurology, vol. 186, no. 2, pp. 134–144, 2004.
[84]
A. R. Simard and S. Rivest, “Bone marrow stem cells have the ability to populate the entire central nervous system into fully differentiated parenchymal microglia,” The FASEB Journal, vol. 18, no. 9, pp. 998–1000, 2004.
[85]
R. M. Ransohoff and V. H. Perry, “Microglial physiology: unique stimuli, specialized responses,” Annual Review of Immunology, vol. 27, pp. 119–145, 2009.
[86]
D. W. Dickson, J. Farlo, P. Davies, H. Crystal, P. Fuld, and S. H. C. Yen, “Alzheimer's disease. A double-labeling immunohistochemical study of senile plaques,” American Journal of Pathology, vol. 132, no. 1, pp. 86–101, 1988.
[87]
S. Haga, K. Akai, and T. Ishii, “Demonstration of microglial cells in and around senile (neuritic) plaques in the Alzheimer brain. An immunohistochemical study using a novel monoclonal antibody,” Acta Neuropathologica, vol. 77, no. 6, pp. 569–575, 1989.
[88]
L. S. Perlmutter, S. A. Scott, E. Barron, and H. C. Chui, “MHC class II-positive microglia in human brain: association with Alzheimer lesions,” Journal of Neuroscience Research, vol. 33, no. 4, pp. 549–558, 1992.
[89]
J. Wegiel, H. Imaki, K. C. Wang et al., “Origin and turnover of microglial cells in fibrillar plaques of APPsw transgenic mice,” Acta Neuropathologica, vol. 105, no. 4, pp. 393–402, 2003.
[90]
R. G. Nagele, J. Wegiel, V. Venkataraman, H. Imaki, K. C. Wang, and J. Wegiel, “Contribution of glial cells to the development of amyloid plaques in Alzheimer's disease,” Neurobiology of Aging, vol. 25, no. 5, pp. 663–674, 2004.
[91]
T. M. Malm, M. Koistinaho, M. P？repalo et al., “Bone-marrow-derived cells contribute to the recruitment of microglial cells in response to β-amyloid deposition in APP/PS1 double transgenic Alzheimer mice,” Neurobiology of Disease, vol. 18, no. 1, pp. 134–142, 2005.
[92]
A. R. Simard, D. Soulet, G. Gowing, J. P. Julien, and S. Rivest, “Bone marrow-derived microglia play a critical role in restricting senile plaque formation in Alzheimer's disease,” Neuron, vol. 49, no. 4, pp. 489–502, 2006.
[93]
F. M. LaFerla, K. N. Green, and S. Oddo, “Intracellular amyloid-β in Alzheimer's disease,” Nature Reviews Neuroscience, vol. 8, no. 7, pp. 499–509, 2007.
[94]
G. M. Shankar, S. Li, T. H. Mehta et al., “Amyloid-β protein dimers isolated directly from Alzheimer's brains impair synaptic plasticity and memory,” Nature Medicine, vol. 14, no. 8, pp. 837–842, 2008.
[95]
H. Jang, F. T. Arce, R. Capone, S. Ramachandran, R. Lal, and R. Nussinov, “Misfolded amyloid ion channels present mobile β-sheet subunits in contrast to conventional ion channels,” Biophysical Journal, vol. 97, no. 11, pp. 3029–3037, 2009.
[96]
P. Chakrabarty, K. Jansen-West, A. Beccard et al., “Massive gliosis induced by interleukin-6 suppresses Aβ deposition in vivo: evidence against inflammation as a driving force for amyloid deposition,” The FASEB Journal, vol. 24, no. 2, pp. 548–559, 2010.
[97]
S. A. Grathwohl, R. E. K？lin, T. Bolmont et al., “Formation and maintenance of Alzheimer's disease beta-amyloid plaques in the absence of microglia,” Nature Neuroscience, vol. 12, no. 11, pp. 1361–1363, 2009.
[98]
J. Prange-Kiel, H. Jarry, M. Schoen et al., “Gonadotropin-releasing hormone regulates spine density via its regulatory role in hippocampal estrogen synthesis,” Journal of Cell Biology, vol. 180, no. 2, pp. 417–426, 2008.
[99]
R. H. Swerdlow, J. M. Burns, and S. M. Khan, “The Alzheimer's disease mitochondrial cascade hypothesis,” Journal of Alzheimer's Disease, vol. 20, supplement 2, pp. S265–S279, 2010.
[100]
D. H. Cho, T. Nakamura, and S. A. Lipton, “Mitochondrial dynamics in cell death and neurodegeneration,” Cellular and Molecular Life Sciences, vol. 67, no. 20, pp. 3435–3447, 2010.
[101]
T. Nakamura, P. Cieplak, D. H. Cho, A. Godzik, and S. A. Lipton, “S-Nitrosylation of Drp1 links excessive mitochondrial fission to neuronal injury in neurodegeneration,” Mitochondrion, vol. 10, no. 5, pp. 573–578, 2010.
[102]
D. J. Selkoe, “Soluble oligomers of the amyloid β-protein impair synaptic plasticity and behavior,” Behavioural Brain Research, vol. 192, no. 1, pp. 106–113, 2008.
[103]
R. D. Brinton, “Investigative models for determining hormone therapy-induced outcomes in brain: evidence in support of a healthy cell bias of estrogen action,” Annals of the New York Academy of Sciences, vol. 1052, pp. 57–74, 2005.
[104]
R. D. Brinton, “The healthy cell bias of estrogen action: mitochondrial bioenergetics and neurological implications,” Trends in Neurosciences, vol. 31, no. 10, pp. 529–537, 2008.
[105]
B. B. Sherwin and J. F. Henry, “Brain aging modulates the neuroprotective effects of estrogen on selective aspects of cognition in women: a critical review,” Frontiers in Neuroendocrinology, vol. 29, no. 1, pp. 88–113, 2008.
