Polypeptoid polymers: Synthesis, characterization, and properties.

Polypeptoids, a class of peptidomimetic polymers, have emerged at the forefront of macromolecular and supramolecular science and engineering as the technological relevance of these polymers continues to be demonstrated. The chemical and structural diversity of polypeptoids have enabled access to and adjustment of a variety of physicochemical and biological properties (eg, solubility, charge characteristics, chain conformation, HLB, thermal processability, degradability, cytotoxicity and immunogenicity). These attributes have made this synthetic polymer platform a potential candidate for various biomedical and biotechnological applications. This review will provide an overview of recent development in synthetic methods to access polypeptoid polymers with well-defined structures and highlight some of the fundamental physicochemical and biological properties of polypeptoids that are pertinent to the future development of functional materials based on polypeptoids.

Cationic Polypeptoids with Optimized Molecular Characteristics toward Efficient Nonviral Gene Delivery.

The rational design of gene vectors relies on the understanding of their structure-property relationship. Polypeptoids, which are structural isomers of natural polypeptides, hold great potential as gene delivery vectors due to their facile preparation, structural tunability, and most importantly, their desirable proteolytic stability. We herein designed a library of polypeptoids with different cationic side-chain terminal groups, degree of polymerizations (DPs), side-chain lengths, and incorporated aliphatic side chains, to unravel the structure-property relationships so that gene delivery efficiency can be maximized and cytotoxicity can be minimized. In HeLa cells, a polypeptoid bearing a primary amine side-chain terminal group exhibited remarkably higher transfection efficiency than that of its analogues containing secondary, tertiary, or quaternary amine groups. Elongation of the polypeptoid backbone length (from 28 to 251 mer) led to enhanced DNA condensation as well as cellular uptake levels, however it also caused higher cytotoxicity. Upon a proper balance between DNA uptake and cytotoxicity, the polypeptoid with a DP of 46 afforded the highest transfection efficiency. Elongating the aliphatic spacer between the backbone and side amine groups enhanced the hydrophobicity of the side chains, which resulted in notably increased membrane activities and transfection efficiency. Further incorporation of hydrophobic decyl side chains led to an improvement in transfection efficiency of ∼6 fold. The top-performing material identified, P11, mediated successful gene transfection under serum-containing conditions, outperforming the commercial transfection reagent poly(ethylenimine) by nearly 4 orders of magnitude. Reflecting its excellent serum-resistant properties, P11 further enabled effective transfection in vivo following intratumoral injection to melanoma-bearing mice. This study will help the rational design of polypeptoid-based gene delivery materials, and the best-performing material identified may provide a potential supplement to existing gene vectors.

YAC128 Huntington's disease transgenic mice show enhanced short-term hippocampal synaptic plasticity early in the course of the disease.

Huntington's disease (HD) is a progressive and fatal neurodegenerative disorder caused by a polyglutamine expansion in the gene encoding the protein huntingtin. The disease progresses over decades, but often patients develop cognitive impairments that precede the onset of the classical motor symptoms. Similar to the disease progression in humans, the yeast artificial chromosome (YAC) 128 HD mouse model also exhibits cognitive dysfunction that precedes the onset of the neuropathological and motor impairments characteristic of HD. Thus, the purpose of this study was to evaluate whether short- and long-term synaptic plasticity in the hippocampus, two related biological models of learning and memory processes, were altered in YAC128 mice in early stages of disease progression. We show that the YAC128 hippocampal dentate gyrus (DG) displays marked reductions in paired-pulse depression both at 3 and 6 months of age. In addition, significantly enhanced post-tetanic and short-term potentiation are apparent in YAC128 mice after high-frequency stimulation at this time. Early and late forms of long-term plasticity were not altered at this stage. Together these findings indicate that there may be elevated neurotransmitter release in response to synaptic stimulation in YAC128 mice during the initial phase of disease progression. These abnormalities in short-term plasticity detected at this stage in YAC128 HD transgenic mice indicate that aberrant information processing at the level of the synapses may contribute, at least in part, to the early onset of cognitive deficits that are characteristic of this devastating neurodegenerative disorder.

Hippocampal neurogenesis levels predict WATERMAZE search strategies in the aging brain.

The hippocampus plays a crucial role in the formation of spatial memories, and it is thought that adult hippocampal neurogenesis may participate in this form of learning. To better elucidate the relationship between neurogenesis and spatial learning, we examined both across the entire life span of mice. We found that cell proliferation, neuronal differentiation, and neurogenesis significantly decrease with age, and that there is an abrupt reduction in these processes early on, between 1.5-3 months of age. After this, the neurogenic capacity continues to decline steadily. The initial abrupt decline in adult neurogenesis was paralleled by a significant reduction in Morris Water Maze performance, however overall learning and memory remained constant thereafter. Further analysis of the search strategies employed revealed that reductions in neurogenesis in the aging brain were strongly correlated with the adoption of spatially imprecise search strategies. Overall, performance measures of learning and memory in the Morris Water Maze were maintained at relatively constant levels in aging animals due to an increase in the use of spatially imprecise search strategies.

Neurogenesis in Huntington's disease: can studying adult neurogenesis lead to the development of new therapeutic strategies?

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by an unstable expansion of CAG repeats in the HD gene. The symptoms include cognitive dysfunction and severe motor impairments. The neuropathology is characterized by neuronal loss mainly in the striatum and cortex, although other regions including the hippocampus are also affected. In this review we discuss the different mouse models of HD, and how the process of neurogenesis in the dentate gyrus (DG) of the hippocampus and the subventricular zone (SVZ) is affected in each. Deficits in adult hippocampal neurogenesis have been repeatedly shown in different genetic models of HD, raising the possibility that an impairment of the neurogenic process might underlie some of the cognitive deficits associated with this neurodegenerative disorder. On the other hand, an increase in SVZ neurogenesis has been observed in human HD brains while no differences in SVZ cell proliferation have been detected in the mouse models. In this review we will discuss the discrepancies between these findings as well as the several mechanisms that might contribute to a dysregulation of adult neurogenesis in HD. Finally, we will provide an overview of the various therapeutic strategies aimed at stimulating the endogenous neurogenic capacity that have been tested in HD genetic models. Ultimately, the insights obtained from these and future studies will greatly improve our understanding of the cognitive impairment characteristic of HD.

Altered adult hippocampal neurogenesis in the YAC128 transgenic mouse model of Huntington disease.

Perturbations in neurogenesis in the adult brain have been implicated in impaired learning and memory. In the present study, we investigated which stages of the neurogenic process are affected in the transgenic YAC128 mouse model of Huntington disease (HD). Hippocampal neuronal proliferation was altered in the dentate gyrus (DG) of YAC128 mice as compared with wild-type (WT) littermate controls in early symptomatic to end-stage mice. In addition, we detected a significantly lower number of immature neurons in the DG of young, pre-symptomatic YAC128 mice. This decrease in neuronal differentiation persisted through the progression of the disease, and resulted in an overall reduction in the number of new mature neurons in the DG of YAC128 mice. There were no changes in cell proliferation and differentiation in the subventricular zone (SVZ). In this study, we demonstrate decreases in neurogenesis in the DG of YAC128 mice, and these deficits may contribute to the cognitive abnormalities observed in these animals.

Running reduces stress and enhances cell genesis in aged mice.

Cell proliferation and neurogenesis are diminished in the aging mouse dentate gyrus. However, it is not known whether isolated or social living affects cell genesis and stress levels in old animals. To address this question, aged (17-18 months old) female C57Bl/6 mice were single or group housed, under sedentary or running conditions. We demonstrate that both individual and socially housed aged C57Bl/6 mice have comparable basal cell proliferation levels and demonstrate increased running-induced cell genesis. To assess stress levels in young and aged mice, corticosterone (CORT) was measured at the onset of the active/dark cycle and 4h later. In young mice, no differences in CORT levels were observed as a result of physical activity or housing conditions. However, a significant increase in stress in socially housed, aged sedentary animals was observed at the onset of the dark cycle; CORT returned to basal levels 4h later. Together, these results indicate that voluntary exercise reduces stress in group housed aged animals and enhances hippocampal cell proliferation.

Characterization of the neurogenesis quiescent zone in the rodent brain: effects of age and exercise.

Although it is accepted that new neurons continue to be generated in the hippocampal dentate gyrus (DG) throughout adulthood, it has recently become apparent that this process is not homogeneous, and that a small region of the DG lacks neurogenesis. Here, we show that the relative area of this neurogenesis quiescent zone (NQZ) did not vary after the peak in hippocampal postnatal neurogenesis and until animals reached adulthood, although the ratio between its actual volume and the total volume of the DG doubled during this time. However, we were able to identify a few mitotic cells that reside within this subregion in early adolescent rats. Furthermore, these cells can be activated, and 1 week of voluntary exercise was enough to significantly increase the number of mitotic cells within the NQZ of adolescent rats. There was, however, no corresponding increase in the number of new neurons in this subregion of the DG, suggesting that some factor necessary to allow these cells to develop into a mature phenotype is missing. Moreover, the same intervention was ineffective in increasing either proliferation or neurogenesis in older adult rats. Surprisingly, we found no evidence for the existence of an NQZ in the mouse DG, suggesting that the neurogenic process in these two rodent species is differently regulated. Understanding the molecular mechanisms underlying the existence of the NQZ in the rat DG might shed light on the processes that regulate adult neurogenesis and its modulation by factors such as aging and exercise.