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

ABSTRACT: 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.

SUBMITTER: Bolognin S

PROVIDER: S-EPMC3889170 | biostudies-literature | 2012 Jan

REPOSITORIES: biostudies-literature

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

Bolognin Silvia S Blanchard Julie J Wang Xiaochuan X Basurto-Islas Gustavo G Tung Yunn Chyn YC Kohlbrenner Erik E Grundke-Iqbal Inge I Iqbal Khalid K

Acta neuropathologica 20111115 1

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 ...[more]

PMID: 22083255

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Project description:Despite years of research, there are no disease-modifying drugs for Alzheimer's disease (AD), a fatal, age-related neurodegenerative disorder. Screening for potential therapeutics in rodent models of AD has generally relied on testing compounds before pathology is present, thereby modeling disease prevention rather than disease modification. Furthermore, this approach to screening does not reflect the clinical presentation of AD patients which could explain the failure to translate compounds identified as beneficial in animal models to disease modifying compounds in clinical trials. Clearly a better approach to pre-clinical drug screening for AD is required.To more accurately reflect the clinical setting, we used an alternative screening strategy involving the treatment of AD mice at a stage in the disease when pathology is already advanced. Aged (20-month-old) transgenic AD mice (APP/swePS1?E9) were fed an exceptionally potent, orally active, memory enhancing and neurotrophic molecule called J147. Cognitive behavioral assays, histology, ELISA and Western blotting were used to assay the effect of J147 on memory, amyloid metabolism and neuroprotective pathways. J147 was also investigated in a scopolamine-induced model of memory impairment in C57Bl/6J mice and compared to donepezil. Details on the pharmacology and safety of J147 are also included.Data presented here demonstrate that J147 has the ability to rescue cognitive deficits when administered at a late stage in the disease. The ability of J147 to improve memory in aged AD mice is correlated with its induction of the neurotrophic factors NGF (nerve growth factor) and BDNF (brain derived neurotrophic factor) as well as several BDNF-responsive proteins which are important for learning and memory. The comparison between J147 and donepezil in the scopolamine model showed that while both compounds were comparable at rescuing short term memory, J147 was superior at rescuing spatial memory and a combination of the two worked best for contextual and cued memory.J147 is an exciting new compound that is extremely potent, safe in animal studies and orally active. J147 is a potential AD therapeutic due to its ability to provide immediate cognition benefits, and it also has the potential to halt and perhaps reverse disease progression in symptomatic animals as demonstrated in these studies.

Project description:Patients with Alzheimer's disease vary in their ability to sustain cognitive abilities in the presence of brain pathology. A major open question is which brain mechanisms may support higher reserve capacity, i.e. relatively high cognitive performance at a given level of Alzheimer's pathology. Higher functional MRI-assessed functional connectivity of a hub in the left frontal cortex is a core candidate brain mechanism underlying reserve as it is associated with education (i.e. a protective factor often associated with higher reserve) and attenuated cognitive impairment in prodromal Alzheimer's disease. However, no study has yet assessed whether such hub connectivity of the left frontal cortex supports reserve throughout the evolution of pathological brain changes in Alzheimer's disease, including the presymptomatic stage when cognitive decline is subtle. To address this research gap, we obtained cross-sectional resting state functional MRI in 74 participants with autosomal dominant Alzheimer's disease, 55 controls from the Dominantly Inherited Alzheimer's Network and 75 amyloid-positive elderly participants, as well as 41 amyloid-negative cognitively normal elderly subjects from the German Center of Neurodegenerative Diseases multicentre study on biomarkers in sporadic Alzheimer's disease. For each participant, global left frontal cortex connectivity was computed as the average resting state functional connectivity between the left frontal cortex (seed) and each voxel in the grey matter. As a marker of disease stage, we applied estimated years from symptom onset in autosomal dominantly inherited Alzheimer's disease and cerebrospinal fluid tau levels in sporadic Alzheimer's disease cases. In both autosomal dominant and sporadic Alzheimer's disease patients, higher levels of left frontal cortex connectivity were correlated with greater education. For autosomal dominant Alzheimer's disease, a significant left frontal cortex connectivity × estimated years of onset interaction was found, indicating slower decline of memory and global cognition at higher levels of connectivity. Similarly, in sporadic amyloid-positive elderly subjects, the effect of tau on cognition was attenuated at higher levels of left frontal cortex connectivity. Polynomial regression analysis showed that the trajectory of cognitive decline was shifted towards a later stage of Alzheimer's disease in patients with higher levels of left frontal cortex connectivity. Together, our findings suggest that higher resilience against the development of cognitive impairment throughout the early stages of Alzheimer's disease is at least partially attributable to higher left frontal cortex-hub connectivity.

Dataset Information

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

Publications

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

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