Article

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

Gladstone Institute of Neurological Disease and Gladstone Institute of Cardiovascular Disease, The J. David Gladstone Institutes, 1650 Owens Street, San Francisco, CA 94158, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.81). 02/2008; 105(4):1343-6. DOI: 10.1073/pnas.0709906104
Source: PubMed

ABSTRACT Convergent evidence has revealed an association between insulin resistance and Alzheimer's disease (AD), and the peroxisome proliferator-activated receptor-gamma (PPAR-gamma) 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-gamma-specific antagonist, GW9662, suggesting that rosiglitazone exerts this effect by activating the PPAR-gamma 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.

0 Bookmarks
 · 
67 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: We present a new hypothesis on the contribution of a dysfunction of the oxidative phosphorylation system, through a decrease in the de novo synthesis of pyrimidine nucleotides, to the pathogenesis of late onset Alzheimer's disease (AD). In the light of this proposition, different treatments for AD patients, such as enhancing the electron flow downstream the coenzyme Q10 of the mitochondrial respiratory chain or increasing mitochondrial biogenesis or directly providing pyrimidines, would be possible. AD is a multifactorial disorder and not all patients would benefit from these treatments. Those healthy individuals harboring mtDNA haplotypes related to a coupled OXPHOS function would probably be the better candidates for these preventive therapies.
    Journal of Alzheimer's disease: JAD 07/2014; · 3.61 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Neuronal processes (neurites and axons) have an important role in brain cells communication and, generally, they are damaged in neurodegenerative diseases. Recent evidence has showed that the activation of PPARγ pathway promoted neuronal differentiation and axon polarity. In addition, activation of PPARγ using thiazolidinediones (TZDs) prevented neurodegeneration by reducing neuronal death, improving mitochondrial function, and decreasing neuroinflammation in neuropathic pain. In this review, we will discuss important evidence that supports a possible role of PPARγ in neuronal development, improvement of neuronal health, and pain signaling. Therefore, activation of PPARγ is a potential target with therapeutic applications against neurodegenerative disorders, brain injury, and pain regulation.
    PPAR Research 08/2014; 2014:768594. · 2.69 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: TOMMORROW is a Phase III delay of onset clinical trial to determine whether low doses of pioglitazone, a molecule that induces mitochondrial doubling, delays the onset of MCI-AD in normal subjects treated with low dose compared to placebo. BOLD imaging studies in rodents and man were used to find the dose that increases oxygen consumption at central regions of the brain in higher proportion than activation of large corticol regions. The trial is made practical by the use of a pharmacogenetic algorithm based on TOMM40 and APOE genotypes and age to identify normal subjects at high risk of MCI-AD between the ages of 65-83 years within a five year follow-up period.
    Current Opinion in Pharmacology 02/2014; 14C:81-89. · 4.23 Impact Factor

Full-text (2 Sources)

Download
14 Downloads
Available from
May 22, 2014