Peripheral Administration Of Peptide Research Articles

P4‐224: Rescue of cognitive impairment and neuronal plasticity with a neurotrophic peptide in a rat model of sporadic Alzheimer's disease

The hippocampus, which is the most affected in Alzheimer's disease (AD), is also a brain area where neurogenesis is known to take place throughout life. AD brain attempts to replace the lost with new neurons but the newborn cells, probably because of an unsuitable neurotrophic microenvironment, fail to mature into functional neurons (Li, B et al., J Neuropathol Exp Neurol 67:78-84, 2008). Additionally, AD is associated with a chronic progressive loss of neuronal plasticity in most of the cerebral cortex. Thus, one therapeutic approach to AD is the pharmacologic enhancement of neurogenesis and neuronal plasticity. A rat model of sporadic AD in which adeno associated virus vector is used to express N-terminal and C-terminal fragments of inhibitor-2 of protein phosphatase-2A, I 2NTF-CTF, and in which abnormal hyperphosphorylation and aggregation of tau and intraneuronal Ab are seen at ∼12 months, was used in this study (Bolognin et al., Acta Neuropathol 123:133-151, 2012). The 2-5 month AAV1-I 2NTF-CTF and, as a control, AAV1-GFP rats were treated with 400 nmoles/kg body weight of Peptide 6 or vehicle only (saline) daily injection for six weeks; Peptide 6 is a ciliary neurotrophic factor mimetic peptide that we previously showed to enhance neurogenesis and neuroplasticity, and improve cognition of normal adult mice (Chohan et al., Neurobiol. Aging 32:1420-1434, 2011), 3xTg-AD triple transgenic AD mice (Blanchard et al., Acta Neuropathol 120:605-621, 2010), and trisomic Ts65Dn Down mice (Blanchard et al., J Neuropathol Exp Neurol 70:1070-1079, 2011). Peripheral administration of Peptide 6 rescued cognitive impairment which was associated with increase in mRNA of brain derived neurotrophic factor and dentate gyrus neurogenesis. Moreover, the I 2NTF-CTF rats treated with Peptide 6 showed a significant increase in markers of neuronal plasticity. These studies suggest (i) a therapeutic potential of Peptide 6 and (ii) a proof of principle of treatment of AD by enhancing neuroregeneration.

Rescue of Synaptic Failure and Alleviation of Learning and Memory Impairments in a Trisomic Mouse Model of Down Syndrome

Down syndrome (DS) is caused by the triplication of ∼240 protein-coding genes on chromosome 21 and is the most prevalent form of developmental disability. This condition results in abnormalities in many organ systems, as well as in intellectual retardation. Many previous efforts to understand brain dysfunction in DS have indicated that cognitive deficits are coincident with reduced synaptic plasticity and decreased neuronal proliferation. One therapeutic strategy for optimizing the microenvironment for neuronal proliferation and synaptic plasticity in the brain is the use of neurotrophins to restore the homeostasis of the brain biochemical milieu. Here, we show that peripheral administration of Peptide 6, an 11-mer corresponding to an active region of ciliary neurotrophic factor, amino acid residues 146 to 156, can inhibit learning and memory impairments in Ts65Dn mice, a trisomic mouse model of DS. Long-term treatment with Peptide 6 enhanced the pool of neural progenitor cells in the hippocampus and increased levels of synaptic proteins crucial for synaptic plasticity. These findings suggest a therapeutic potential of Peptide 6 in promoting functional neural integration into networks, thereby strengthening biologic substrates of memory processing.

An experimental rat model of sporadic Alzheimer’s disease and rescue of cognitive impairment with a neurotrophic peptide

Alzheimer's disease (AD) is multifactorial and, to date, no single cause of the sporadic form of this disease, which accounts for over 99% of the cases, has been established. In AD brain, protein phosphatase-2A (PP2A) activity is known to be compromised due to the cleavage and translocation of its potent endogenous inhibitor, I2PP2A, from the neuronal nucleus to the cytoplasm. Here, we show that adeno-associated virus vector-induced expression of the N-terminal I2NTF and C-terminal I2CTF halves of I2PP2A , also called SET, in brain reproduced key features of AD in Wistar rats. The I2NTF-CTF rats showed a decrease in brain PP2A activity, abnormal hyperphosphorylation and aggregation of tau, a loss of neuronal plasticity and impairment in spatial reference and working memories. To test whether early pharmacologic intervention with a neurotrophic molecule could rescue neurodegeneration and behavioral deficits, 2.5-month-old I2NTF-CTF rats and control littermates were treated for 40 days with Peptide 6, an 11-mer peptide corresponding to an active region of the ciliary neurotrophic factor. Peripheral administration of Peptide 6 rescued neurodegeneration and cognitive deficit in I2NTF-CTF animals by increasing dentate gyrus neurogenesis and mRNA level of brain derived neurotrophic factor. Moreover, Peptide 6-treated I2NTF-CTF rats showed a significant increase in dendritic and synaptic density as reflected by increased expression of synapsin I, synaptophysin and MAP2, especially in the pyramidal neurons of CA1 and CA3 of the hippocampus.

Pharmacologic reversal of neurogenic and neuroplastic abnormalities and cognitive impairments without affecting Aβ and tau pathologies in 3xTg-AD mice

In addition to the occurrence of numerous neurofibrillary tangles and Aβ plaques, neurogenesis and neuronal plasticity are markedly altered in Alzheimer disease (AD). Although the most popular therapeutic approach has been to inhibit neurodegeneration, another is to promote neurogenesis and neuronal plasticity by utilizing the regenerative capacity of the brain. Here we show that, in a transgenic mouse model of AD, 3xTg-AD mice, there was a marked deficit in neurogenesis and neuroplasticity, which occurred before the formation of any neurofibrillary tangles or Aβ plaques and was associated with cognitive impairment. Furthermore, peripheral administration of Peptide 6, an 11-mer, which makes an active region of ciliary neurotrophic factor (CNTF, amino acid residues 146-156), restored cognition by enhancing neurogenesis and neuronal plasticity in these mice. Although this treatment had no detectable effect on Aβ and tau pathologies in 9-month animals, it enhanced neurogenesis in dentate gyrus, reduced ectopic birth in the granular cell layer, and increased neuronal plasticity in the hippocampus and cerebral cortex. These findings, for the first time, demonstrate the possibility of therapeutic treatment of AD and related disorders by peripheral administration of a peptide corresponding to a biologically active region of CNTF.

The nutrient balance hypothesis: peptides, sympathetic activity, and food intake.

Food intake can be increased or decreased after either central or peripheral administration of peptides. Galanin, neuropeptide Y, opioid peptides, growth hormone releasing hormone and desacetyl-MSH increase food intake whereas insulin, glucagon, cholecystokinin, anorectin, corticotropin releasing hormone, neurotensin, bombesin, enterostatin, cyclo-his-pro and thyrotropin-releasing hormone reduce food intake. A number of these peptides also affect the activity of the sympathetic nervous system. The peptides which have been tested have a reciprocal effect on food intake and sympathetic activity. Opioids, NPY and GHRH, which increase food intake, decrease sympathetic activity. Conversely, peptides which reduce food intake, increase sympathetic activity, with glucagon, cholecystokinin, corticotropin releasing hormone, calcitonin, neurotensin and bombesin being examples, Several of these peptides also affect the intake of specific nutrients. Insulin reduces food intake in animals fed a high carbohydrate diet, but not when fed a high fat diet. Neuropeptide Y increases carbohydrate intake. Galanin and opioid peptides increase fat intake. Enterostatin and cyclo-His-Pro, on the other hand reduce fat intake. Glucagon decreases protein intake. The effect of peptides on the intake of specific nutrients suggests that peptides may work in part by modulating basic feeding mechanisms to lead to the selection of specific nutrients from the diet. This hypothesis might be called a nutrient specific model of peptide-induced food intake.