Passive immunization targeting the N-terminal region of phosphorylated tau (residues 68-71) improves spatial memory in okadaic acid induced tauopathy model rats.

Alzheimer's disease (AD) is the leading cause of dementia, characterized by progressive loss of memory and other cognitive functions. The cognitive impairment in patients with AD is closely associated with loss of synapses and the formation of neurofibrillary tangles (NFT) containing hyperphosphorylated tau in the hippocampus. Effective treatment for AD is still not available. In this study, the sequence comprising of residues 50-71 in the N-terminal region of tau, containing theoretically predicted B- and T-cell epitopes in close proximity to pathologically relevant phospho-serine (residue 68) and phospho-threonine (residues 69, 71) was selected as a potential immunotherapeutic peptide. This 22-residue long phospho-peptide (50TPTEDGSEEPGSETSDAKpSpTPpT71) was custom synthesized and its therapeutic potential was tested in experimental rats. For this purpose, adult Sprague-Dawley rats were intranasally treated with okadaic acid (OA), a selective inhibitor of protein phosphatase PP2A. Within a day of OA administration, these rats showed marked impairment in cognitive functions with a significant increase in p-tau/t-tau ratio in the hippocampal homogenates. Passive immunization studies conducted in these OA treated rats with polyclonal anti-phospho-peptide antibodies resulted in a significant improvement in learning and memory functions in Barne's maze task. Further, p-tau levels in the hippocampal homogenates were reduced. In addition, these antibodies effectively prevented the aggregation of recombinant tau in vitro. These results demonstrate that targeting N-terminal region of tau harbouring the phospho-residue cluster 68-71 would be beneficial and may present an effective therapeutic opportunity for AD and other tauopathies.

Cognition enhancing effect of the aqueous extract of Cinnamomum zeylanicum on non-transgenic Alzheimer's disease rat model: Biochemical, histological, and behavioural studies.

OBJECTIVE: Several dietary supplements are actively being tested for their dual role of alleviating the metabolic perturbations and restricting the consequent cognitive dysfunctions seen in neurodegenerative disorders such as Alzheimer's disease (AD). The aim of the current study was to assess the influence of aqueous extract of cinnamon (CE) on the monosodium glutamate-induced non-transgenic rat model of AD (NTAD) established with insulin resistance, hyperglycaemia, neuronal loss, and cognitive impairment at a very early stage of life. METHODS: The experimental design included oral administration of CE (50 mg/kg body weight) for 20 weeks to 2-month and 10-month-old NTAD rats. Following the treatments, the animals attained 7 and 15 months of age, respectively. They were then subjected to behavioural testing, biochemical analysis, and stereology experiments. RESULTS: The results demonstrated that CE treatment improved the insulin sensitivity, increased phosphorylated glycogen synthase kinase-3ß (pGSK3ß), inhibited the cholinesterase activity, and improved the learning ability in NTAD rats. Histological evaluation has shown an increase in neuron count in the DG sub-field of hippocampus upon treatment with CE. DISCUSSION: These beneficial effects of CE are suggestive of considering cinnamon as a dietary supplement in modulating the metabolic changes and cognitive functions.

The Neuroprotective Effect of Dark Chocolate in Monosodium Glutamate-Induced Nontransgenic Alzheimer Disease Model Rats: Biochemical, Behavioral, and Histological Studies.

The vulnerability to oxidative stress and cognitive decline continue to increase during both normal and pathological aging. Dietary changes and sedentary life style resulting in mid-life obesity and type 2 diabetes, if left uncorrected, further add to the risk of cognitive decline and Alzheimer disease (AD) in the later stages of life. Certain antioxidant agents such as dietary polyphenols, taken in adequate quantities, have been suggested to improve the cognitive processes. In this study, we examined the effect of oral administration of dark chocolate (DC) containing 70% cocoa solids and 4% total polyphenol content for three months at a dose of 500 mg/Kg body weight per day to 17-month-old monosodium glutamate treated obese Sprague-Dawley rats, earlier characterized as a nontransgenic AD (NTAD) rat model after reversal of obesity, diabetes, and consequent cognitive impairments. The results demonstrated that DC reduced the hyperglycemia, inhibited the cholinesterase activity in the hippocampal tissue homogenates, and improved the cognitive performance in spatial memory related Barnes maze task. Histological studies revealed an increase in cell volume in the DC treated rats in the CA3 region of the hippocampus. These findings demonstrated the benefits of DC in enhancing cognitive function and cholinergic activity in the hippocampus of the aged NTAD rats while correcting their metabolic disturbances.

Combination of Spirulina with glycyrrhizin prevents cognitive dysfunction in aged obese rats.

OBJECTIVES: To evaluate the cognition enhancing effect of the combination of Spirulina and glycyrrhizin in monosodium glutamate (MSG)-induced obese aged rats. MATERIALS AND METHODS: Obesity was induced in rats by administration of MSG (intraperitoneally, 4 mg/g body weight) for 14 consecutive days from day 1 after birth. Subsequently, the animals were allowed to grow for 18 months with food and water ad libitum. Hypercholesterolemia, hyperglycemia, leptin resistance, were monitored in these animals. Cognitive status was assessed by Barne's maze task and hippocampal acetylcholinesterase (AChE) levels. Further, the animals were treated with Spirulina (Sp) (oral route, 1 g/Kg body weight, for 30 days) alone or glycyrrhizin (Gly) alone (intraperitoneal route, 0.1 mg/Kg, on day 15 and day 21), or their combination (SpGly). Counting of the treatment days was done by considering first day of Sp administration as day 1. After the completion of 30 days of Spirulina treatment or 2 doses of Gly administration or the combination (SpGly) treatment, the animals were left for 3 weeks. They were then were assessed for their biochemical and cognitive changes. RESULTS: The combination of Sp with Gly showed a significant reduction (P < 0.0001) in glucose, cholesterol, leptin levels in the serum with improvement in cognitive functions with concomitant reduction in AChE activity in the hippocampal tissue homogenates (P < 0.0001) of the obese rats. CONCLUSION: SpGly combination has a potential role in reversing cognitive dysfunctions associated with aging and obesity.

Amyloid beta lowering and cognition enhancing effects of ghrelin receptor analog [D-Lys (3)] GHRP-6 in rat model of obesity.

Obesity arising due to the dietary and life style changes is fast reaching epidemic proportions all over the world. There is increasing evidence that the incidence of Alzheimer disease (AD) is significantly influenced by a cluster of metabolic diseases, including diabetes and obesity. This study was aimed to test the suitability of experimentally-induced obesity in rats as an experimental animal model of AD. We used the procedure of neonatal administration of rats with monosodium L-glutamate (MSG), which generates adult obese animals as our study design and assessed the AD-like changes by measuring amyloid beta (1-42) and acetylcholinesterase (AChE) levels in the hippocampal extracts and cognitive impairments by Barnes maze task. Further, we investigated the influence of anti-obesity substance [D-Lys (3)] GHRP-6 on blood glucose, hippocampal Abeta, AChE levels and restoration of cognitive deficits. Results revealed that administration of MSG to neonatal rats exhibited increased body mass index and serum glucose levels over the controls. Measurement of markers for AD-like molecular changes i.e. amyloid beta (Abeta) and AChE levels showed marked elevation in these two parameters in the hippocampus of MSG-treated rats. Assessment of cognitive abilities by Barnes maze revealed spatial disorientation characteristic of AD. Administration of ghrelin receptor analog [D-Lys (3)] GHRP-6 to obese rats resulted in significant restoration of serum cholesterol, glucose, leptin and ghrelin levels to that of control with concomitant reduction in hippocampal Abeta and AChE levels. In addition, the treated animals exhibited marked improvement in Barne's maze task. These findings suggest that MSG-induced obese rats may serve as non-transgenic animal model for AD research. Further, the results indicate the potential of [D-Lys (3)] GHRP-6 as a promising anti-Alzheimer candidate.

Influence of conformational antibodies on dissociation of fibrillar amyloid beta (A beta 1-42) in vitro.

Many neurodegenerative diseases result due to the accumulation of misfolded proteins as amyloid fibrils. Although the protein components of these fibrils from different disease states differ considerably, they appear to share common structure. Among these conformational disorders, Alzheimer's disease (AD) and prion diseases exhibit significant overlap in their mechanism of pathogenesis. The present report demonstrates that antibodies directed against the prion protein repeat motif, Tyr-Tyr-Arg motif, recognize recombinantly expressed human amyloid beta (A beta) aggregates in enzyme linked immunosorbent assay. In addition, these antibodies dissociate the preformed aggregates of A beta in vitro. These findings illustrate an important property of conformation dependent antibodies viz., they specifically recognize the protein deposits associated with pathology and not the protein in normal tissue. These antibodies may benefit the development of approaches towards prevention and treatment of protein misfolding diseases.