Skip to main content
  • Submit
  • About
    • Editorial Board
    • PNAS Staff
    • FAQ
    • Accessibility Statement
    • Rights and Permissions
    • Site Map
  • Contact
  • Journal Club
  • Subscribe
    • Subscription Rates
    • Subscriptions FAQ
    • Open Access
    • Recommend PNAS to Your Librarian
  • Log in
  • My Cart

Main menu

  • Home
  • Articles
    • Current
    • Special Feature Articles - Most Recent
    • Special Features
    • Colloquia
    • Collected Articles
    • PNAS Classics
    • List of Issues
  • Front Matter
  • News
    • For the Press
    • This Week In PNAS
    • PNAS in the News
  • Podcasts
  • Authors
    • Information for Authors
    • Editorial and Journal Policies
    • Submission Procedures
    • Fees and Licenses
  • Submit
  • About
    • Editorial Board
    • PNAS Staff
    • FAQ
    • Accessibility Statement
    • Rights and Permissions
    • Site Map
  • Contact
  • Journal Club
  • Subscribe
    • Subscription Rates
    • Subscriptions FAQ
    • Open Access
    • Recommend PNAS to Your Librarian

User menu

  • Log in
  • My Cart

Search

  • Advanced search
Home
Home

Advanced Search

  • Home
  • Articles
    • Current
    • Special Feature Articles - Most Recent
    • Special Features
    • Colloquia
    • Collected Articles
    • PNAS Classics
    • List of Issues
  • Front Matter
  • News
    • For the Press
    • This Week In PNAS
    • PNAS in the News
  • Podcasts
  • Authors
    • Information for Authors
    • Editorial and Journal Policies
    • Submission Procedures
    • Fees and Licenses

New Research In

Physical Sciences

Featured Portals

  • Physics
  • Chemistry
  • Sustainability Science

Articles by Topic

  • Applied Mathematics
  • Applied Physical Sciences
  • Astronomy
  • Computer Sciences
  • Earth, Atmospheric, and Planetary Sciences
  • Engineering
  • Environmental Sciences
  • Mathematics
  • Statistics

Social Sciences

Featured Portals

  • Anthropology
  • Sustainability Science

Articles by Topic

  • Economic Sciences
  • Environmental Sciences
  • Political Sciences
  • Psychological and Cognitive Sciences
  • Social Sciences

Biological Sciences

Featured Portals

  • Sustainability Science

Articles by Topic

  • Agricultural Sciences
  • Anthropology
  • Applied Biological Sciences
  • Biochemistry
  • Biophysics and Computational Biology
  • Cell Biology
  • Developmental Biology
  • Ecology
  • Environmental Sciences
  • Evolution
  • Genetics
  • Immunology and Inflammation
  • Medical Sciences
  • Microbiology
  • Neuroscience
  • Pharmacology
  • Physiology
  • Plant Biology
  • Population Biology
  • Psychological and Cognitive Sciences
  • Sustainability Science
  • Systems Biology
Research Article

Rosiglitazone increases dendritic spine density and rescues spine loss caused by apolipoprotein E4 in primary cortical neurons

Jens Brodbeck, Maureen E. Balestra, Ann M. Saunders, Allen D. Roses, Robert W. Mahley, and Yadong Huang
PNAS January 29, 2008 105 (4) 1343-1346; https://doi.org/10.1073/pnas.0709906104
Jens Brodbeck
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Maureen E. Balestra
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Ann M. Saunders
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Allen D. Roses
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Robert W. Mahley
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • For correspondence: yhuang@gladstone.ucsf.edu rmahley@gladstone.ucsf.edu
Yadong Huang
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • For correspondence: yhuang@gladstone.ucsf.edu rmahley@gladstone.ucsf.edu
  1. Contributed by Robert W. Mahley, October 18, 2007 (received for review July 20, 2007)

  • Article
  • Figures & SI
  • Info & Metrics
  • PDF
Loading

Abstract

Convergent evidence has revealed an association between insulin resistance and Alzheimer's disease (AD), and the peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist, rosiglitazone, an insulin sensitizer and mitochondrial activator, improves cognition in patients with early or mild-to-moderate AD. Apolipoprotein (apo) E4, a major genetic risk factor for AD, exerts neuropathological effects through multiple pathways, including impairment of dendritic spine structure and mitochondrial function. Here we show that rosiglitazone significantly increased dendritic spine density in a dose-dependent manner in cultured primary cortical rat neurons. This effect was abolished by the PPAR-γ-specific antagonist, GW9662, suggesting that rosiglitazone exerts this effect by activating the PPAR-γ pathway. Furthermore, the C-terminal-truncated fragment of apoE4 significantly decreased dendritic spine density. Rosiglitazone rescued this detrimental effect. Thus, rosiglitazone might improve cognition in AD patients by increasing dendritic spine density.

  • Alzheimer's disease
  • mitochondria
  • peroxisome proliferator-activated receptor-γ
  • apolipoprotein E fragment
  • synaptogenesis

Alzheimer's disease (AD), a devastating neurodegenerative disease that usually develops in the sixth decade of life, affects millions of people globally (1). Alarmingly, currently available treatments provide no more than a temporary improvement of functional deficits. Thus, AD cases will increase disproportionately as the global elderly population increases. A major risk factor for late-onset AD is apolipoprotein (apo) E4, which increases the risk and lowers the age of onset in a gene dose-dependent manner (2, 3). The three isoforms of human apoE (apoE2, apoE3, and apoE4) have different roles in lipid metabolism and neurobiology (4–8). ApoE3 promotes neurite outgrowth, dendritic arborization, and synaptogenesis, whereas apoE4 inhibits these processes both in vitro (9–11) and in vivo (12–14). Furthermore, apoE4 transgenic mice have deficits in synaptic plasticity, synaptic terminal remodeling, synaptogenesis, and learning and memory (12–16). Loss of synaptophysin-immunoreactive presynaptic terminals, indicating synaptic loss (12, 17), occurs early in AD and is considered the best pathological correlate of cognitive decline (18–20).

Previously, we showed that neurons express apoE in response to injury (21) and that neuronal apoE is cleaved into C-terminal-truncated fragments resembling those in AD brains (22). ApoE4 is more susceptible to this cleavage than apoE3 (23, 24). ApoE4 fragments are neurotoxic in vitro and cause neurodegeneration and behavioral deficits in transgenic mice (22–24). In neurons, truncated apoE4 escapes the secretory pathway, enters the cytosol, and interacts with tau, increasing its phosphorylation and causing preneurofibrillary tangles (22, 23). In the cytosol, apoE4 fragments also interact with the mitochondria, impairing their membrane potential and function (25). Mitochondrial impairment in AD is greater in apoE4 than in apoE3 carriers (26). Thus, apoE4 may contribute to AD pathogenesis by causing mitochondrial dysfunction and synaptic deficits (6).

Type 2 diabetes also increases the risk of developing AD (27–29), particularly among diabetic patients carrying apoE4 (30). Insulin resistance, the core defect in type 2 diabetes, results in hyperinsulinemia to compensate for the reduced action of insulin in peripheral tissues (31). Correspondingly, AD patients are at increased risk for elevated plasma insulin levels and insulin resistance (32, 33). In addition, AD brains from autopsied patients have markedly lower levels of insulin mRNA and tyrosine phosphorylation than control brains (34). Indeed, inhibition of the neuronal insulin receptor has been proposed as a model for sporadic AD (35). Thus, type 2 diabetes and AD might share a common pathogenic feature that can be modified by apoE genotype.

The thiazolidinediones (e.g., troglitazone, pioglitazone, and rosiglitazone) are agonists of the nuclear receptor peroxisome proliferator-activated receptor-γ (PPAR-γ). Because they increase peripheral insulin sensitivity and stimulate mitochondrial biogenesis and function (36, 37), thiazolidinediones are widely used to treat type 2 diabetes (38, 39). In clinical trials, rosiglitazone improved cognition in a subset of AD patients (40, 41) and also reduced learning and memory deficits in a mouse model of AD (42). However, the mechanisms underlying the potential beneficial effects of rosiglitazone in AD remain unclear. In this study, we tested the hypothesis that rosiglitazone increases dendritic spine density and rescues the dendritic spine loss caused by apoE4.

Results

Rosiglitazone Increases Dendritic Spine Density.

To assess the effect of the PPAR-γ agonist, rosiglitazone, on dendritic spine density, we incubated primary cortical rat neurons, previously cultured for 14–17 days in vitro, with DMSO control or 5 μM rosiglitazone for 24 h. Four to 7 days before the experiment, the cells were transfected with EGFP-tagged β-actin (EGFP–β-actin), a cytoskeletal protein that is abundant in dendritic spines (43). EGFP–β-actin expression does not impair neuronal function or synaptic morphology (44). Rosiglitazone increased dendritic spine density, visible at both low (Fig. 1A) and high (Fig. 1B) magnification of representative neurons and dendrites, respectively, as shown by microscopic analysis. Quantitative analyses showed 58.5 ± 3% greater dendritic spine density in treated neurons than in controls (Fig. 1C). However, rosiglitazone did not affect other parameters of neuronal plasticity, including the area of the dendritic field (estimated by counting the proximal extensions of the dendritic tree), dendrite length (longest distance between the soma and the proximal dendritic extension), and the number of dendritic branch points (extensions originating from primary dendrites) (Fig. 2).

Fig. 1.
  • Download figure
  • Open in new tab
  • Download powerpoint
Fig. 1.

Rosiglitazone increases dendritic spine density in rat primary cortical neurons. Spine density is defined as the number of spines per micrometer of dendrite length. The cells, transiently transfected with the synaptic marker EGFP–β-actin and cultured for 14–17 days, were incubated with 5 μM rosiglitazone for 24 h or DMSO only as a control. (A) Representative images showing the stimulatory effect of rosiglitazone on dendritic spine density. (B) Representative dendrites from three different neurons. (C) Dendritic spine densities of eight randomly selected cells per condition were quantified. Values are mean ± SEM. *, P < 0.01 versus control (two-tailed t test).

Fig. 2.
  • Download figure
  • Open in new tab
  • Download powerpoint
Fig. 2.

Rosiglitazone does not alter the area of the dendritic field, dendrite length, and the number of dendritic branch points. The cells, transiently transfected with the synaptic marker EGFP–β-actin and cultured for 14–17 days, were incubated with 5 μM rosiglitazone for 24 h or DMSO only as a control. The area of dendritic field (A), dendrite length (B), and the number of dendritic branches (C) from 15 randomly selected cells per condition were quantified. Values are mean ± SEM.

Rosiglitazone's Effects on Dendritic Spine Density Are Dose-Dependent.

Next, we performed dose–response studies to test the efficacy of rosiglitazone in increasing dendritic spine density. After 14–17 days in culture, primary cortical neurons were incubated with 0.1, 0.5, 5, and 10 μM rosiglitazone at 37°C for 24 h. A comparison of the dentritic complexity of neurons incubated with rosiglitazone versus control suggested no toxic effects at all concentrations used. Dendritic spine density was increased by 29.6 ± 5.2% at a dose of 0.5 μM and by 47.03 ± 3.4% at 5 μM (Fig. 3). No further increase was seen at 10 μM.

Fig. 3.
  • Download figure
  • Open in new tab
  • Download powerpoint
Fig. 3.

Dose-dependent effect of rosiglitazone on dendritic spine density in rat primary cortical neurons. The cells, transiently transfected with the synaptic marker EGFP–β-actin and cultured for 14–17 days, were incubated for 24 h with rosiglitazone in the presence or absence of 1 μM PPAR-γ antagonist GW9662 or DMSO only as a control. Dendritic spine densities of eight randomly selected cells per condition were quantified. Values are mean ± SEM. *, P < 0.05; **, P < 0.01 versus control (two-tailed t test).

Rosiglitazone Increases Dendritic Spine Density by Activating the PPAR-γ Pathway.

Depending on the concentration, thiazolidinediones exert both PPAR-γ-dependent and PPAR-γ-independent effects (45). To assess the specificity of rosiglitazone's effect on dendritic spine density, we cultured primary cortical neurons for 14–17 days and incubated them with 5 μM rosiglitazone and 1 μM PPAR-γ-specific antagonist GW9662 at 37°C for 24 h. GW9662 abolished the rosiglitazone-induced increase in dendritic spine density (Fig. 3).

Rosiglitazone Rescues the Dendritic Spine Loss Caused by ApoE4.

ApoE4 and C-terminal-truncated fragments of apoE4 [apoE4(1–272), lacking the C-terminal 27 aa] impair cytoskeletal structure and mitochondrial function (12, 22, 23, 25). Because cytoskeletal integrity and mitochondrial function are critical for normal synaptic morphology and function (46, 47), we tested the effects of various forms of apoE on dendritic spine density in primary cortical neurons. ApoE4 significantly reduced dendritic spine density by 25.5 ± 4%, and the apoE4(1–272) fragment reduced it by 45.6 ± 3%, compared with apoE3 (Fig. 4). Thus, apoE4 and, to a greater extent, its fragment appear to impair synaptogenesis or synaptic maintenance. Rosiglitazone rescued the dendritic spine loss caused by apoE4(1–272) (Fig. 4). Rosiglitazone also abolished the difference in dendritic spine density between apoE4 and apoE3, although the effect did not reach statistical significance, compared with apoE4 alone (Fig. 4).

Fig. 4.
  • Download figure
  • Open in new tab
  • Download powerpoint
Fig. 4.

Rosiglitazone rescues dendritic spine loss caused by the apoE4 fragment. Rat primary cortical neurons, transiently transfected with the synaptic marker EGFP–β-actin and cultured for 14–17 days, were incubated with 7.5 μg/ml apoE (various forms) for 24 h in the presence or absence of 5 μM rosiglitazone. Dendritic spine densities of 10 cells per condition were quantified. Values are mean ± SEM.

Discussion

This study shows that the PPAR-γ agonist, rosiglitazone, increases the density of dendritic spines on cultured primary rat neurons in a dose-dependent manner. In addition, rosiglitazone rescued the loss of dendritic spines caused by the C-terminal-truncated fragments of apoE4.

In clinical trials, rosiglitazone had beneficial effects in patients with early or mild-to-moderate AD (40, 41). Rosiglitazone also reduced learning and memory deficits in a mouse model of AD (42). Our data suggest that rosiglitazone improves cognition by increasing dendritic spine density. In one trial, rosiglitazone at once-daily doses of 2, 4, and 8 mg improved cognition in AD patients carrying apoE3, but not in those carrying apoE4 (41). However, rosiglitazone clearly prevented the dendritic spine loss caused by the apoE4 fragments in primary neuronal cultures. Because rosiglitazone does not readily cross the blood–brain barrier at least in rodents (40), this discrepancy may indicate that the lower doses of rosiglitazone used in AD patients might not achieve brain levels high enough to overcome the detrimental effects of apoE4 and its fragments despite a potentially compromised blood–brain barrier.

PPAR-γ agonists, such as rosiglitazone, have a complex pharmacology beyond their established peripheral effect in activating the PPAR-γ pathway. For instance, they appear to have diverse roles in neuroprotection, such as promoting the expression of the mitochondrial uncoupling protein 2 after ischemia-induced hippocampal injury (48) and suppressing the proinflammatory transcription factor NF-κB through PPAR-γ-dependent (49, 50) or PPAR-γ-independent pathways (51). This finding raises the question of whether the effects of rosiglitazone on dendritic spine density are related to its ability to activate PPAR-γ or other actions. We found that the PPAR-γ-specific antagonist, GW9662, abolished the rosiglitazone-induced increase in dendritic spine density, strongly suggesting that it exerts beneficial effects by activating the PPAR-γ pathway. Further studies are required to elucidate the precise mechanism.

How does rosiglitazone increase dendritic spine density and rescue dendritic spine loss induced by apoE4? One possibility is that rosiglitazone stimulates mitochondrial biogenesis and function (37, 52, 53). Normal mitochondrial dynamics and function are essential for generating and maintaining distinct axonal and dendritic microdomains in response to local metabolic demand (47). Moreover, failure of mitochondria to traffic to appropriate sites causes energy starvation and impairs synaptogenesis and memory formation (47, 54). Thus, rosiglitazone might increase mitochondrial biogenesis or function, thereby improving synaptogenesis or maintenance of dendritic spines. Furthermore, because apoE4 fragments impair mitochondrial integrity and function (25), the rescue of dendritic spine loss also might reflect the beneficial effects of rosiglitazone on mitochondrial biogenesis or function.

Materials and Methods

Reagents.

Rosiglitazone maleate was provided by GlaxoSmithKline. Recombinant apoE3, apoE4, and apoE4(1–272) were provided by Karl Weisgraber (The J. David Gladstone Institutes). The pPDGF–EGFP–β-actin construct was a gift of Yukiko Goda (University College London, London, U.K.). All plasmids were purified with the Plasmid Maxi kit from Qiagen. GW9662, a PPAR-γ antagonist, was from Sigma–Aldrich.

Primary Neuron Culture and Transfection.

Cortices from neonatal rat pups postnatal day 1 were dissected, treated for 30 min with 10 units/ml papain (Worthington Biochemical), and incubated with 10 μg/ml trypsin inhibitor for 15 min. After trituration, dissociated neurons were plated on 12-mm glass coverslips (Fisher Scientific) coated with poly-l-lysine at 8 × 105 cells per square centimeter. After 2 h, cells were transferred into neurobasal medium supplemented with B27, 1 mM l-glutamine, and 100 μg/ml penicillin/streptomycin (Invitrogen). Neurons were routinely transfected after 10 days in culture and used for experiments 4–7 days after transfection. Cells were maintained in a humidified incubator with 5% CO2 at 37°C. The neurons were transfected with 2 μg of pPDGF–EGFP–β-actin construct with 3 μl of Lipofectamine 2000 (Invitrogen).

Treatment with Rosiglitazone and ApoE.

After 14–17 days in culture, primary cortical rat neurons were incubated with the rosiglitazone concentrations indicated in Fig. 3 or DMSO as a control with or without 1 μM GW9662 or 7.5 μg/ml apoE (various forms) at 37°C for 24 h.

Confocal Microscopy.

After treatment, the neurons were fixed for 20 min in ice-cold 4% paraformaldehyde in PBS (pH 7.4) and mounted on microscope slides with VECTAshield (Vector Laboratories). Digital images of EGFP were collected on a laser-scanning confocal microscope with a Bio-Rad Radiance 2000 scanhead mounted on an Optiphot-2 microscope (Nikon) with a ×60 oil objective lens.

Image Analyses.

To determine dendritic spine densities, high-resolution digital images were analyzed with National Institutes of Health ImageJ software (http://rsb.info.nih.gov/ij). The length of dendrites was measured by tracing their extension using the segmented line selection. Dendritic spines were counted manually by using the point picker function of the particle analysis plug-in. The complexity of the dendritic tree was quantified by using the ImageJ NeuronJ plug-in to trace dendritic branches. The area of the dendritic field was estimated by connecting the outmost dendritic extensions and calculating the area of the resulting polygon.

Statistical Analysis.

A two-tailed t test assuming equal variances was used for statistical analyses. P < 0.05 was considered statistically significant.

Acknowledgments

We thank Dr. Karl Weisgraber for providing purified apoE3, apoE4, and apoE4(1–272); Dr. Yukiko Goda for providing the EGFP–β-actin construct; Karina Fantillo and Sylvia Richmond for manuscript preparation; John Carroll for graphics; and Stephen Ordway and Gary Howard for editorial assistance. This work was supported by The J. David Gladstone Institutes and GlaxoSmithKline Research and Development.

Footnotes

  • **To whom correspondence may be addressed. E-mail: yhuang{at}gladstone.ucsf.edu or rmahley{at}gladstone.ucsf.edu
  • Author contributions: J.B., A.D.R., R.W.M., and Y.H. designed research; J.B. and M.E.B. performed research; J.B., M.E.B., A.M.S., A.D.R., R.W.M., and Y.H. analyzed data; M.E.B. and A.M.S. contributed new reagents/analytic tools; and J.B., A.D.R., R.W.M., and Y.H. wrote the paper.

  • The authors declare no conflict of interest.

  • Freely available online through the PNAS open access option.

  • © 2008 by The National Academy of Sciences of the USA

References

  1. ↵
    1. Mayeux R
    (2003) Annu Rev Neurosci 26:81–104.
    OpenUrlPubMed
  2. ↵
    1. Corder EH,
    2. Saunders AM,
    3. Strittmatter WJ,
    4. Schmechel DE,
    5. Gaskell PC,
    6. Small GW,
    7. Roses AD,
    8. Haines JL,
    9. Pericak-Vance MA
    (1993) Science 261:921–923.
    OpenUrlAbstract/FREE Full Text
  3. ↵
    1. Saunders AM,
    2. Strittmatter WJ,
    3. Schmechel D,
    4. St George-Hyslop PH,
    5. Pericak-Vance MA,
    6. Joo SH,
    7. Rosi BL,
    8. Gusella JF,
    9. Crapper-MacLachlan DR,
    10. Alberts MJ,
    11. et al.
    (1993) Neurology 43:1467–1472.
    OpenUrlAbstract/FREE Full Text
  4. ↵
    1. Mahley RW
    (1988) Science 240:622–630.
    OpenUrlAbstract/FREE Full Text
  5. ↵
    1. Huang Y,
    2. Weisgraber KH,
    3. Mucke L,
    4. Mahley RW
    (2004) J Mol Neurosci 23:189–204.
    OpenUrlCrossRefPubMed
  6. ↵
    1. Mahley RW,
    2. Weisgraber KH,
    3. Huang Y
    (2006) Proc Natl Acad Sci USA 103:5644–5651.
    OpenUrlAbstract/FREE Full Text
  7. ↵
    1. Huang Y
    (2006) Neurology 66(Suppl 1):S79–S85.
    OpenUrlAbstract/FREE Full Text
  8. ↵
    1. Huang Y
    (2006) Curr Opin Drug Discovery Dev 9:627–641.
    OpenUrlPubMed
  9. ↵
    1. Nathan BP,
    2. Bellosta S,
    3. Sanan DA,
    4. Weisgraber KH,
    5. Mahley RW,
    6. Pitas RE
    (1994) Science 264:850–852.
    OpenUrlAbstract/FREE Full Text
  10. ↵
    1. Bellosta S,
    2. Nathan BP,
    3. Orth M,
    4. Dong L-M,
    5. Mahley RW,
    6. Pitas RE
    (1995) J Biol Chem 270:27063–27071.
    OpenUrlAbstract/FREE Full Text
  11. ↵
    1. Teter B,
    2. Xu P-T,
    3. Gilbert JR,
    4. Roses AD,
    5. Galasko D,
    6. Cole GM
    (1999) J Neurochem 73:2613–2616.
    OpenUrlCrossRefPubMed
  12. ↵
    1. Buttini M,
    2. Orth M,
    3. Bellosta S,
    4. Akeefe H,
    5. Pitas RE,
    6. Wyss-Coray T,
    7. Mucke L,
    8. Mahley RW
    (1999) J Neurosci 19:4867–4880.
    OpenUrlAbstract/FREE Full Text
  13. ↵
    1. Buttini M,
    2. Yu G-Q,
    3. Shockley K,
    4. Huang Y,
    5. Jones B,
    6. Masliah E,
    7. Mallory M,
    8. Yeo T,
    9. Longo FM,
    10. Mucke L
    (2002) J Neurosci 22:10539–10548.
    OpenUrlAbstract/FREE Full Text
  14. ↵
    1. Levi O,
    2. Jongen-Relo AL,
    3. Feldon J,
    4. Roses AD,
    5. Michaelson DM
    (2003) Neurobiol Dis 13:273–282.
    OpenUrlCrossRefPubMed
  15. ↵
    1. Raber J,
    2. Wong D,
    3. Buttini M,
    4. Orth M,
    5. Bellosta S,
    6. Pitas RE,
    7. Mahley RW,
    8. Mucke L
    (1998) Proc Natl Acad Sci USA 95:10914–10919.
    OpenUrlAbstract/FREE Full Text
  16. ↵
    1. Levi O,
    2. Jongen-Relo AL,
    3. Feldon J,
    4. Michaelson DM
    (2005) J Neurol Sci 229–230:241–248.
    OpenUrl
  17. ↵
    1. Mucke L,
    2. Masliah E,
    3. Yu G-Q,
    4. Mallory M,
    5. Rockenstein EM,
    6. Tatsuno G,
    7. Hu K,
    8. Kholodenko D,
    9. Johnson-Wood K,
    10. McConlogue L
    (2000) J Neurosci 20:4050–4058.
    OpenUrlAbstract/FREE Full Text
  18. ↵
    1. DeKosky ST,
    2. Scheff SW
    (1990) Ann Neurol 27:457–464.
    OpenUrlCrossRefPubMed
  19. ↵
    1. Terry RD,
    2. Masliah E,
    3. Salmon DP,
    4. Butters N,
    5. DeTeresa R,
    6. Hill R,
    7. Hansen LA,
    8. Katzman R
    (1991) Ann Neurol 30:572–580.
    OpenUrlCrossRefPubMed
  20. ↵
    1. Masliah E,
    2. Mallory M,
    3. Alford M.,
    4. DeTeresa R,
    5. Hansen LA,
    6. McKeel DW, Jr,
    7. Morris JC
    (2001) Neurology 56:127–129.
    OpenUrlAbstract/FREE Full Text
  21. ↵
    1. Xu Q,
    2. Bernardo A,
    3. Walker D,
    4. Kanegawa T,
    5. Mahley RW,
    6. Huang Y
    (2006) J Neurosci 26:4985–4994.
    OpenUrlAbstract/FREE Full Text
  22. ↵
    1. Huang Y,
    2. Liu XQ,
    3. Wyss-Coray T,
    4. Brecht WJ,
    5. Sanan DA,
    6. Mahley RW
    (2001) Proc Natl Acad Sci USA 98:8838–8843.
    OpenUrlAbstract/FREE Full Text
  23. ↵
    1. Harris FM,
    2. Brecht WJ,
    3. Xu Q,
    4. Tesseur I,
    5. Kekonius L,
    6. Wyss-Coray T,
    7. Fish JD,
    8. Masliah E,
    9. Hopkins PC,
    10. Scearce-Levie K,
    11. et al.
    (2003) Proc Natl Acad Sci USA 100:10966–10971.
    OpenUrlAbstract/FREE Full Text
  24. ↵
    1. Brecht WJ,
    2. Harris FM,
    3. Chang S,
    4. Tesseur I,
    5. Yu G-Q,
    6. Xu Q,
    7. Fish JD,
    8. Wyss-Coray T,
    9. Buttini M,
    10. Mucke L,
    11. et al.
    (2004) J Neurosci 24:2527–2534.
    OpenUrlAbstract/FREE Full Text
  25. ↵
    1. Chang S,
    2. Ma TR,
    3. Miranda RD,
    4. Balestra ME,
    5. Mahley RW,
    6. Huang Y
    (2005) Proc Natl Acad Sci USA 102:18694–18699.
    OpenUrlAbstract/FREE Full Text
  26. ↵
    1. Gibson GE,
    2. Haroutunian V,
    3. Zhang H,
    4. Park LCH,
    5. Shi Q,
    6. Lesser M,
    7. Mohs RC,
    8. Sheu RK-F,
    9. Blass JP
    (2000) Ann Neurol 48:297–303.
    OpenUrlCrossRefPubMed
  27. ↵
    1. Leibson CL,
    2. Rocca WA,
    3. Hanson VA,
    4. Cha R,
    5. Kokmen E,
    6. O'Brien PC,
    7. Palumbo PJ
    (1997) Am J Epidemiol 145:301–308.
    OpenUrlAbstract/FREE Full Text
  28. ↵
    1. Luchsinger JA,
    2. Tang M-X,
    3. Stern Y,
    4. Shea S,
    5. Mayeux R
    (2001) Am J Epidemiol 154:635–641.
    OpenUrlAbstract/FREE Full Text
  29. ↵
    1. Arvanitakis Z,
    2. Wilson RS,
    3. Bienias JL,
    4. Evans DA,
    5. Bennett DA
    (2004) Arch Neurol 61:661–666.
    OpenUrlCrossRefPubMed
  30. ↵
    1. Peila R,
    2. Rodriguez BL,
    3. Launer LJ
    (2002) Diabetes 51:1256–1262.
    OpenUrlAbstract/FREE Full Text
  31. ↵
    1. Goldstein BJ
    (2002) Am J Cardiol 90:3G–10G.
    OpenUrlPubMed
  32. ↵
    1. Craft S,
    2. Dagogo-Jack SE,
    3. Wiethop BV,
    4. Murphy C,
    5. Nevins RT,
    6. Fleischman S,
    7. Rice V,
    8. Newcomer JW,
    9. Cryer PE
    (1993) Behav Neurosci 107:926–940.
    OpenUrlCrossRefPubMed
  33. ↵
    1. Watson GS,
    2. Craft S
    (2003) CNS Drugs 17:27–45.
    OpenUrlCrossRefPubMed
  34. ↵
    1. Steen E,
    2. Terry BM,
    3. Rivera EJ,
    4. Cannon JL,
    5. Neely TR,
    6. Tavares R,
    7. Xu XJ,
    8. Wands JR,
    9. de la Monte SM
    (2005) J Alzheimers Dis 7:63–80.
    OpenUrlPubMed
  35. ↵
    1. Hoyer S,
    2. Lee SK,
    3. Löffler T,
    4. Schliebs R
    (2000) Ann NY Acad Sci 920:256–258.
    OpenUrlPubMed
  36. ↵
    1. Day C
    (1999) Diabetic Med 16:179–192.
    OpenUrlCrossRefPubMed
  37. ↵
    1. Feinstein DL,
    2. Spagnolo A,
    3. Akar C,
    4. Weinberg G,
    5. Murphy P,
    6. Gavrilyuk V,
    7. Russo CD
    (2005) Biochem Pharmacol 70:177–188.
    OpenUrlCrossRefPubMed
  38. ↵
    1. Lehmann JM,
    2. Moore LB,
    3. Smith-Oliver TA,
    4. Wilkison WO,
    5. Wilson TM,
    6. Kliewer SA
    (1995) J Biol Chem 270:12953–12956.
    OpenUrlAbstract/FREE Full Text
  39. ↵
    1. Berger J,
    2. Bailey P,
    3. Biswas C,
    4. Cullinan CA,
    5. Doebber TW,
    6. Hayes NS,
    7. Saperstein R,
    8. Smith RG,
    9. Leibowitz MD
    (1996) Endocrinology 137:4189–4195.
    OpenUrlCrossRefPubMed
  40. ↵
    1. Watson GS,
    2. Cholerton BA,
    3. Reger MA,
    4. Baker LD,
    5. Plymate SR,
    6. Asthana S,
    7. Fishel MA,
    8. Kulstad JJ,
    9. Green PS,
    10. Cook DG,
    11. et al.
    (2005) Am J Geriatr Psychiatry 13:950–958.
    OpenUrlCrossRefPubMed
  41. ↵
    1. Risner ME,
    2. Saunders AM,
    3. Altman JFB,
    4. Ormandy GC,
    5. Craft S,
    6. Foley IM,
    7. Zvartau-Hind ME,
    8. Hosford DA,
    9. Roses AD
    (2006) Pharmacogenomics J 6:246–254.
    OpenUrlCrossRefPubMed
  42. ↵
    1. Pedersen WA,
    2. McMillan PJ,
    3. Kulstad JJ,
    4. Leverenz JB,
    5. Craft S,
    6. Haynatzki GR
    (2006) Exp Neurol 199:265–273.
    OpenUrlCrossRefPubMed
  43. ↵
    1. Dillon C,
    2. Goda Y
    (2005) Annu Rev Neurosci 28:25–55.
    OpenUrlCrossRefPubMed
  44. ↵
    1. Morales M,
    2. Colicos MA,
    3. Goda Y
    (2000) Neuron 27:539–550.
    OpenUrlCrossRefPubMed
  45. ↵
    1. Lea MA,
    2. Sura M,
    3. Desbordes C
    (2004) Anticancer Res 24:3–9.
    OpenUrl
  46. ↵
    1. Tesseur I,
    2. Van Dorpe J,
    3. Bruynseels K,
    4. Bronfman F,
    5. Sciot R,
    6. Van Lommel A,
    7. Van Leuven F
    (2000) Am J Pathol 157:1495–1510.
    OpenUrlCrossRefPubMed
  47. ↵
    1. Li Z,
    2. Okamoto K-I,
    3. Hayashi Y,
    4. Sheng M
    (2004) Cell 119:873–887.
    OpenUrlCrossRefPubMed
  48. ↵
    1. Chen S-D,
    2. Wu H-Y,
    3. Yang D-I,
    4. Lee S-Y,
    5. Shaw F-Z,
    6. Lin T-K,
    7. Liou C-W,
    8. Chuang Y-C
    (2006) Biochem Biophys Res Commun 351:198–203.
    OpenUrlCrossRefPubMed
  49. ↵
    1. Daynes RA,
    2. Jones DC
    (2002) Nature 2:748–759.
    OpenUrl
  50. ↵
    1. Mohanty P,
    2. Aljada A,
    3. Ghanim H,
    4. Hofmeyer D,
    5. Tripathy D,
    6. Syed T,
    7. Al-Haddad W,
    8. Dhindsa S,
    9. Dandona P
    (2004) J Clin Endocrinol Metab 89:2728–2735.
    OpenUrlCrossRefPubMed
  51. ↵
    1. Chawla A,
    2. Barak Y,
    3. Nagy L,
    4. Liao D,
    5. Tontonoz P,
    6. Evans RM
    (2001) Nat Med 7:48–52.
    OpenUrlCrossRefPubMed
  52. ↵
    1. Wilson-Fritch L,
    2. Burkart A,
    3. Bell G,
    4. Mendelson K,
    5. Leszyk J,
    6. Nicoloro S,
    7. Czech M,
    8. Corvera S
    (2003) Mol Cell Biol 23:1085–1094.
    OpenUrlAbstract/FREE Full Text
  53. ↵
    1. Hondares E,
    2. Mora O,
    3. Yubero P,
    4. Rodriguez de la Concepción M,
    5. Iglesias R,
    6. Giralt M,
    7. Villarroya F
    (2006) Endocrinology 147:2829–2838.
    OpenUrlCrossRefPubMed
  54. ↵
    1. Sullivan PG,
    2. Brown MR
    (2005) Prog Neuropsychopharmacol Biol Psychiatry 29:407–410.
    OpenUrlCrossRefPubMed
PreviousNext
Back to top
Article Alerts
Email Article

Thank you for your interest in spreading the word on PNAS.

NOTE: We only request your email address so that the person you are recommending the page to knows that you wanted them to see it, and that it is not junk mail. We do not capture any email address.

Enter multiple addresses on separate lines or separate them with commas.
Rosiglitazone increases dendritic spine density and rescues spine loss caused by apolipoprotein E4 in primary cortical neurons
(Your Name) has sent you a message from PNAS
(Your Name) thought you would like to see the PNAS web site.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Rosiglitazone increases dendritic spine density and rescues spine loss caused by apolipoprotein E4 in primary cortical neurons
Jens Brodbeck, Maureen E. Balestra, Ann M. Saunders, Allen D. Roses, Robert W. Mahley, Yadong Huang
Proceedings of the National Academy of Sciences Jan 2008, 105 (4) 1343-1346; DOI: 10.1073/pnas.0709906104

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Request Permissions
Share
Rosiglitazone increases dendritic spine density and rescues spine loss caused by apolipoprotein E4 in primary cortical neurons
Jens Brodbeck, Maureen E. Balestra, Ann M. Saunders, Allen D. Roses, Robert W. Mahley, Yadong Huang
Proceedings of the National Academy of Sciences Jan 2008, 105 (4) 1343-1346; DOI: 10.1073/pnas.0709906104
Digg logo Reddit logo Twitter logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Mendeley logo Mendeley
Proceedings of the National Academy of Sciences: 105 (4)
Table of Contents

Submit

Sign up for Article Alerts

Jump to section

  • Article
    • Abstract
    • Results
    • Discussion
    • Materials and Methods
    • Acknowledgments
    • Footnotes
    • References
  • Figures & SI
  • Info & Metrics
  • PDF

You May Also be Interested in

Surgeons hands during surgery
Inner Workings: Advances in infectious disease treatment promise to expand the pool of donor organs
Despite myriad challenges, clinicians see room for progress.
Image credit: Shutterstock/David Tadevosian.
Setting sun over a sun-baked dirt landscape
Core Concept: Popular integrated assessment climate policy models have key caveats
Better explicating the strengths and shortcomings of these models will help refine projections and improve transparency in the years ahead.
Image credit: Witsawat.S.
Double helix
Journal Club: Noncoding DNA shown to underlie function, cause limb malformations
Using CRISPR, researchers showed that a region some used to label “junk DNA” has a major role in a rare genetic disorder.
Image credit: Nathan Devery.
Steamboat Geyser eruption.
Eruption of Steamboat Geyser
Mara Reed and Michael Manga explore why Yellowstone's Steamboat Geyser resumed erupting in 2018.
Listen
Past PodcastsSubscribe
Multi-color molecular model
Enzymatic breakdown of PET plastic
A study demonstrates how two enzymes—MHETase and PETase—work synergistically to depolymerize the plastic pollutant PET.
Image credit: Aaron McGeehan (artist).

Similar Articles

Site Logo
Powered by HighWire
  • Submit Manuscript
  • Twitter
  • Facebook
  • RSS Feeds
  • Email Alerts

Articles

  • Current Issue
  • Special Feature Articles – Most Recent
  • List of Issues

PNAS Portals

  • Anthropology
  • Chemistry
  • Classics
  • Front Matter
  • Physics
  • Sustainability Science
  • Teaching Resources

Information

  • Authors
  • Editorial Board
  • Reviewers
  • Librarians
  • Press
  • Site Map
  • PNAS Updates

Feedback    Privacy/Legal

Copyright © 2021 National Academy of Sciences. Online ISSN 1091-6490