Protection against developmental retardation in apolipoprotein E-deficient mice by a fatty neuropeptide: Implications for early treatment of Alzheimer's disease

Abstract

Stearyl‐Nle‐17‐VIP (SNV) is a novel agonist of vasoactive intestinal peptide (VIP) exhibiting a 100‐fold greater potency than the parent molecule and specificity for a receptor associated with neuronal survival. Here, mice deficient in apolipoprotein E (ApoE), a molecule associated with the etiology of Alzheimer's disease, served as a model to investigate the developmental and protective effects of SNV. In comparison to control animals, the deficient mice exhibited (a) reduced amounts of VIP messenger RNA; (b) decreased cholinergic activity (c) significant retardation in the acquisition of developmental milestones: forelimb placing behavior and cliff avoidance behavior; and (d) learning and memory impairments. Daily injections of SNV to ApoE‐deficient newborn pups resulted in increased cholinergic activity and marked improvements in the time of acquisition of behavioral milestones, with peptide‐treated animals developing as fast as control animals and exhibiting improved cognitive functions after cessation of peptide treatment. Specificity was demonstrated in that treatment with a related peptide (PACAP), pituitary adenylate cyclase‐activating peptide, produced only limited amelioration. As certain genotypes of ApoE increase the probability of Alzheimer's disease, early counseling and preventive treatments may now offer an important route for therapeutics design. © 1997 John Wiley & Sons, Inc. J Neurobiol 33: 329–342, 1997

NAP Enhances Neurodevelopment of Newborn Apolipoprotein E-Deficient Mice Subjected to Hypoxia

“…The outcome measures were behavioral neurodevelopmental abilities with no histopathologic or biochemical measurements. During postnatal development, ApoE-deficient mice exhibited a significant (25%) decrease in brain choline acetyltransferase activity compared with agematched (21-day-old) C57B6 mice (Gozes et al, 1997a). Daily subcutaneous injections of ApoE-deficient mice with NAP resulted in brain choline acetyltransferase activity (at 21 days of age) that was not significantly different from C57B6 mice and was significantly improved compared with untreated ApoE-deficient mice (Bassan et al, 1999).…”

“…ApoE-deficient pup survival rate was higher than C57B6 pups in all subgroups, with NAP treatment having no effect on survival on day 45. ApoE and the ApoE genotype have been associated before as a risk factor for Alzheimer's disease (Poirier, 2005), brain development, and arteriosclerosis (e.g., Gozes et al, 1997a). Here, a lack of ApoE expression in the pups may potentially offer some protective benefit against death associated with ischemia compared with the C57B6 genotype.…”

“…Overexpression of the Alzheimer's related amyloid precursor protein in mice exacerbates hypoxic damage of hippocampal neurons (Ghribi et al, 1999). Neuroprotective treatment has shown behavioral improvement in adult ApoE-deficient mice (Gozes et al, 1997a). Furthermore, intrathecal delivery of an ApoE-derived peptide prevented postischemic brain necrosis following neonatal hypoxic-ischemic injury (McAdoo et al, 2005).…”

“…Furthermore, intrathecal delivery of an ApoE-derived peptide prevented postischemic brain necrosis following neonatal hypoxic-ischemic injury (McAdoo et al, 2005). Previous studies suggested that, during early brain development, the blood-brain barrier is open and that systemically applied (subcutaneously) compounds (including NAP) reach the mouse brain and affect neurodevelopment (e.g., Hill et al, 1991;Gozes et al, 1997a;Bassan et al, 1999).…”

Protective Peptides That Are Orally Active and Mechanistically Nonchiral

“…Memory deficits and cholinergic impairments have been described in adult apolipoprotein E-deficient mice. Furthermore, developing apolipoprotein E-deficient mice have been shown to be cognitively impaired (Gordon et al, 1995;Gozes et al, 1997). Peptides (0.5 mg each) were dissolved in 0.01 M acetic acid (30 l) and further diluted with saline.…”