Nitric Oxide Activity and Isoenzyme Expression in the Senescence-Accelerated Mouse P8 Model of Alzheimer's Disease: Effects of Anti-Amyloid Antibody and Antisense Treatments

Abstract

Amyloid beta protein (Abeta) in Alzheimer's disease induces oxidative stress through several mechanisms, including stimulation of nitric oxide synthase (NOS) activity. We examined NOS activity and expression in the senescence-accelerated mouse P8 (SAMP8) line. The SAMP8 strain develops with aging cognitive impairments, increases in Abeta, and oxidative stress, all reversed by amyloid precursor protein antisense or Abeta antibody treatment. We found here that hippocampal NOS activity in 12-month-old SAMP8 mice was nearly double that of 2-month-old SAMP8 or CD-1 mice, but with no change in NOS isoenzyme mRNA and protein levels. Antisense or antibody treatment further increased NOS activity in aged SAMP8 mice. Antisense treatment increased inducible NOS (iNOS) mRNA levels, decreased neuronal NOS mRNA and protein levels, but did not affect endothelial NOS (eNOS) or iNOS protein or eNOS mRNA levels. These results suggest a complex relation between Abeta and NOS in the SAMP8 that is largely mediated through posttranslational mechanisms.

S100B and ADMA in cerebral small vessel disease and cognitive dysfunction

“…There is also evidence linking ADMA and NO regulation with cognitive dysfunction [57]. Increases in ADMA lead to a decline in NO, which causes reduction in brain blood flow, white matter fiber edema and demyelination, and generation of β-amyloid precursor protein, ultimately leading to learning and memory disorders [58]. Thus, S100B and ADMA may be potential therapeutic targets, and inhibition or blockade of their pathologic effects in patients with elevated levels may help to minimize cognitive impairment.…”

In vitro antioxidant activities of proanthocyanidins extracted from the lotus seedpod and ameliorative effects on learning and memory impairment in scopolamine-induced amnesia mice

“…As a free radical, NO reacts with superoxide radicals to form peroxynitrite and results in neurotoxicity and cell apoptosis under an abnormal physiological status, which is involved in the pathogenesis of AD and Parkinson's disease (27). Previous study has shown that administration of LSPC for 3 months resulted in NO inhibition in the Values are expressed as a mean±SD (n=10).…”

Animal models in the drug discovery pipeline for Alzheimer's disease

“…Interestingly, genes and proteins that undergo significant alterations in SAMP8 brains are related to the following functional categories: neuroprotection, signal transduction, immune response, energy metabolism, mitochondrion, protein folding and degradation, reactive oxygen species production, cytoskeleton and transport, lipid abnormalities and cholinergic dysfunction (Butterfield and Poon, 2005; for review, see Sowell and Butterfield, 2010). The SAMP8 strain has proven to be a relevant model for AD and several treatment strategies have been studied in these mice, including antioxidants (Farr et al ., 2003; Poon et al ., 2005; Nishimura et al ., 2006; Shih et al ., 2010), antisense oligonucleotides, directed at the Aβ region of the amyloid precursor protein (APP) gene (Kumar et al ., 2000; Banks et al ., 2001; Poon et al ., 2004; Ali et al ., 2009), consistent with the notion that SAMP8 cognitive changes are associated with Aβ‐associated oxidative stress. Besides pharmacological interventions, dietary restriction as a way to increase lifespan and improve health, and its effect on various functional categories that are affected in SAMP8 with ageing, as described above, was recently evaluated (Tajes et al ., 2010).…”