Article

Folic Acid potentiates the effect of memantine on spatial learning and neuronal protection in an Alzheimer's disease transgenic model.

Department of Neurology, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan.
Journal of Alzheimer's disease: JAD (Impact Factor: 4.17). 02/2010; 20(2):607-15. DOI: 10.3233/JAD-2010-1396
Source: PubMed

ABSTRACT Folic acid deficiency and hyperhomocysteinemia potentiate amyloid-beta (Abeta) neuron toxicity. Memantine, an NMDA antagonist used in moderate to severe AD, is considered to be neuroprotective. We propose that folic acid might have a synergistic effect for memantine in protecting neurons from Abeta accumulation. We treated 8-month-old Tg2576 transgenic mice with memantine (30 mg/kg/day) with or without folic acid (8 mg/kg/day) for 4 months. Escape latencies in the Morris water maze were significantly shorter in the folic acid-memantine treatment group Tg(+)_M+F compared to both the non-treatment transgenic controls Tg(+) and the memantine-treatment group Tg(+)_M (both p < 0.05). Analysis of Abeta40 and Abeta42 showed lower brain loads in both treatment groups but this did not reach statistical significance. Histopathology analysis showed that Tg(+)_M+F had lower ratios of neuronal damage than Tg(+) (p < 0.001) and Tg(+)_M (p< 0.005). DNA analysis revealed that in the Tg(+)M_+F group, transcription was upregulated in 72 brain genes involved in neurogenesis, neural differentiation, memory, and neurotransmission compared to the Tg(+)_M group. In conclusion, we found that folic acid may potentiate the effect of memantine on spatial learning and neuronal protection. The benefit of combination therapy may be through co-action on the methylation-controlled Abeta production, and modification of brain gene expression.

1 Bookmark
 · 
104 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: In Alzheimer's disease (AD) basic research and drug discovery, mouse models are essential resources for uncovering biological mechanisms, validating molecular targets and screening potential compounds. Both transgenic and non-genetically modified mouse models enable access to different types of AD-like pathology in vivo. Although there is a wealth of genetic and biochemical studies on proposed AD pathogenic pathways, as a disease that centrally features cognitive failure, the ultimate readout for any interventions should be measures of learning and memory. This is particularly important given the lack of knowledge on disease etiology-assessment by cognitive assays offers the advantage of targeting relevant memory systems without requiring assumptions about pathogenesis. A multitude of behavioral assays are available for assessing cognitive functioning in mouse models, including ones specific for hippocampal-dependent learning and memory. Here we review the basics of available transgenic and non-transgenic AD mouse models and detail three well-established behavioral tasks commonly used for testing hippocampal-dependent cognition in mice-contextual fear conditioning, radial arm water maze and Morris water maze. In particular, we discuss the practical considerations, requirements and caveats of these behavioral testing paradigms.
    Biochemical pharmacology 01/2014; · 4.25 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Increased dietary folic acid (FA) is associated with reduced risks of Alzheimer's disease (AD). The AD drug memantine (Mn) has had limited therapeutic effects for the treatment of patients with moderate to severe AD. This study investigated whether and the underlying mechanisms by which the combination of Mn and FA may have synergistic or additive effects in protecting against amyloid-β(25-35) peptide (Aβ)-induced neurocytotoxicity. Aβ treatment of human neuroblastoma SH-SY5Y cells significantly induced a 6-fold increase of apoptotic cells compared with the Aβ-untreated group. Preincubation of Aβ-exposed cells with FA (500 μM) or Mn (20 μM) caused a 22% and 10% reduction of apoptotic cells, respectively, whereas the combo-treatments at such doses synergistically alleviated Aβ-induced apoptosis by 60% (P < 0.05). The apoptotic protection by the combo-treatments coincided with attenuating Aβ-elicited mitochondrial (mt) membrane depolarization and abolishing Aβ-induced mt cytochrome c release to the cytosol. Increased levels of FA at 1000 μM in combination with 20 μM Mn exerted an additive protection against Aβ(25-35)-induced-apoptosis as compared to the isolate Mn group (P < 0.05). The combo-treatments reversed Aβ-elicited mt membrane depolarization, attenuated Aβ-elicited mt cytochrome c release to the cytosol, and diminished Aβ-promoted superoxide generation. The apoptotic-protection by such combo-treatments was partially abolished by carbonyl cyanide 3-chlorophenylhydrazone (mt membrane potential uncoupler) and sodium azide (mt cytochrome c oxidase inhibitor). Taken together, the data demonstrated that dose-dependent FA and Mn synergistically or additively protected SH-SY5Y cells against Aβ-induced apoptosis, which was partially, if not completely, mediated by mt stress-associated death signals.
    Food and chemical toxicology: an international journal published for the British Industrial Biological Research Association 09/2013; · 2.99 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Down syndrome (DS) is a multisystem disorder affecting the cardiovascular, respiratory, gastrointestinal, neurological, hematopoietic, and musculoskeletal systems and is characterized by significant cognitive disability and a possible common pathogenic mechanism with Alzheimer’s disease. During the last decade, numerous studies have supported the notion that the triplication of specific genes on human chromosome 21 plays a significant role in cognitive dysfunction in DS. Here we reviewed studies in trisomic mouse models and humans, including children and adults with DS. In order to identify groups of genes that contribute to cognitive disability in DS, multiple mouse models of DS with segmental trisomy have been generated. Over-expression of these particular genes in DS can lead to dysfunction of several neurotransmitter systems. Therapeutic strategies for DS have either focused on normalizing the expression of triplicated genes with important role in DS or restoring the function of these systems. Indeed, our extensive review of studies on the pathogenesis of DS suggests that one plausible strategy for the treatment of cognitive dysfunction is to target the cholinergic, serotonergic, GABA-ergic, glutamatergic, and norepinephrinergic system. However, a fundamental strategy for treatment of cognitive dysfunction in DS would include reducing to normal levels the expression of specific triplicated genes in affected systems before the onset of neurodegeneration.
    Progress in Neuro-Psychopharmacology and Biological Psychiatry 05/2014; · 3.55 Impact Factor

Full-text

View
79 Downloads
Available from
May 20, 2014