Targeting papez circuit for cognitive dysfunction- insights into deep brain stimulation for Alzheimer's disease.

Hippocampus is the most widely studied brain area coupled with impairment of memory in a variety of neurological diseases and Alzheimer's disease (AD). The limbic structures within the Papez circuit have been linked to various aspects of cognition. Unfortunately, the brain regions that include this memory circuit are often ignored in terms of understanding cognitive decline in these diseases. To properly comprehend where cognition problems originate, it is crucial to clarify any aberrant contributions from all components of a specific circuit -on both a local and a global level. The pharmacological treatments currently available are not long lasting. Deep Brain Stimulation (DBS) emerged as a new powerful therapeutic approach for alleviation of the cognitive dysfunctions. Metabolic, functional, electrophysiological, and imaging studies helped to find out the crucial nodes that can be accessible for DBS. Targeting these nodes within the memory circuit produced significant improvement in learning and memory by disrupting abnormal circuit activity and restoring the physiological network. Here, we provide an overview of the neuroanatomy of the circuit of Papez along with the mechanisms and various deep brain stimulation targets of the circuit structures which could be significant for improving cognitive dysfunctions in AD.

Tau trajectory in Alzheimer's disease: Evidence from the connectome-based computational models.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder with an impairment of cognition and memory. Current research on connectomics have now related changes in the network organization in AD to the patterns of accumulation and spread of amyloid and tau, providing insights into the neurobiological mechanisms of the disease. In addition, network analysis and modeling focus on particular use of graphs to provide intuition into key organizational principles of brain structure, that stipulate how neural activity propagates along structural connections. The utility of connectome-based computational models aids in early predicting, tracking the progression of biomarker-directed AD neuropathology. In this article, we present a short review of tau trajectory, the connectome changes in tau pathology, and the dependent recent connectome-based computational modelling approaches for tau spreading, reproducing pragmatic findings, and developing significant novel tau targeted therapies.

Experimentally induced animal models for cognitive dysfunction and Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterised pathologically by the presence of extracellular amyloid plaques and the intracellular neurofibrillary tangles, along with inflammation, and a compromised antioxidant system. Significant insights into the neurobiology to better understand the pathophysiology of AD and to evaluate the possibility of cutting-edge therapy strategies, can be obtained through the selection of a well-designed experimental animal model. From the transgenic to chemical/drug-induced models, none of them represents the complete picture of Alzheimer pathology and incidence of cognitive dysfunction. Researchers did not explain why one model was preferred over another, did not consider how the pathological phenomena were formed (spontaneously, experimentally, or by genetic manipulation), and did not address the traits of the species that affect the results. There is a lack of concordance between preclinical models and clinical trials that could be due to variety of reasons such as incomplete models, choice of animal species, lack of variability, and the validity of the models. To provide greater translation of preclinical AD studies to clinical trials proper designing of the model is essential. This review provides a brief recap ranging from animal doses to their induction mechanism and common limitations of the chemical-induced AD models. • Animal models may fail to replicate the exact pathology of the disease • Validity of the model is essential for proper translation of pathology from animal models to human disease • Appropriate induction doses need to be administered.

mTOR signaling as a molecular target for the alleviation of Alzheimer's disease pathogenesis.

Mechanistic/mammalian target of rapamycin (mTOR) belongs to the phosphatidylinositol kinase-related kinase (PIKK) family. mTOR signaling is required for the commencement of essential cell functions including autophagy. mTOR primarily governs cell growth in response to favourable nutrients and other growth stimuli. However, it also influences aging and other aspects of nutrient-related physiology such as protein synthesis, ribosome biogenesis, and cell proliferation in adults with very limited growth. The major processes for survival such as synaptic plasticity, memory storage and neuronal recovery involve a significant mTOR activity. mTOR dysregulation is becoming a prevalent motif in a variety of human diseases, including cancer, neurological disorders, and other metabolic syndromes. The use of rapamycin to prolong life in different animal models may be attributable to the multiple roles played by mTOR signaling in various processes involved in ageing, protein translation, autophagy, stem cell pool turnover, inflammation, and cellular senescence. mTOR activity was found to be altered in AD brains and rodent models, supporting the notion that aberrant mTOR activity is one of the key events contributing to the onset and progression of AD hallmarks This review assesses the molecular association between the mTOR signaling pathway and pathogenesis of Alzheimer's disease. The research data supporting this theme are also reviewed.

Potentiation of microglial endocannabinoid signaling alleviates neuroinflammation in Alzheimer's disease.

Alzheimer's disease (AD) isaprogressive neurodegenerative disorder characterized by chronic inflammation due to the presence of neurotoxic Aß and tau proteins. Increased microglial activation and inflated immune response are the other factors to be considered in AD pathology. Microglial cells own biochemical machinery that synthesizes and release endocannabinoids. The exploitation of therapeutic actions of endocannabinoid system has newly emerged in the field of Alzheimer's disease. The activation of cannabinoid receptors/ cannabinoid system modulates inflammatory responses. This review assesses the association between the microglial endocannabinoid system and neuroinflammation in AD. The data supporting the anti-inflammatory role of pharmacological agents modulating cannabinoid system are also reviewed.

Benincasa hispida alleviates amyloid pathology by inhibition of Keap1/Nrf2-axis: Emphasis on oxidative and inflammatory stress involved in Alzheimer's disease model.

OBJECTIVES: Alzheimer's disease is a progressive neurodegenerative disorder with cognitive and memory impairment. Benincasa hispida is being used in the treatment of various neurological diseases in Ayurveda system of medicine. The objective of the study was to investigate the effect of Benincasa hispida fruit extract in the Alzheimer's disease rats. METHODS: Benincasa hispida fruits extract was administered orally for 16 weeks at doses of 250 and 500-mg/kg/day. The cognitive deficits were examined by behavioural tests like Morris water maze test, Y-maze and rota-rod test. Biochemical and neurochemical analysis of Acetylcholine, dopamine, serotonin levels and anti-oxidant, anti-inflammatory markers were evaluated and the mRNA expression of Keap/Nrf2 axis was analysed by RT-PCR. RESULTS: Aluminum chloride (AlCl3) induction altered the behavioural profile and produced significant alterations in the cortical and hippocampal regions of the brain and the treatment with Benincasa hispida extract at doses of 250-mg/kg/day (p<0.05) and 500mg/kg/day (p<0.05) alleviated the acetylcholine, dopamine and serotonin neurotransmitter levels. The antioxidant enzyme markers such as superoxide dismutase (SOD), Catalase (CAT), glutathione (GSH) were increased and the oxidative stress marker malondialdehyde(MDA) was decreased. The inflammatory cytokine levels of TNF-α, IL-1ß were decreased in Alzheimer's disease induced rats. We further estimated Keap/Nrf2/HO-1 genes these anti-oxidant genes were upregulated(p < 0.001) in treatment groups. Further, the neuroprotective activity of Benincasa was further confirmed by histopathological studies of hippocampal CA3 fields. CONCLUSIONS: The findings of the current study indicates Benincasa hispida as a possible neuroprotective alternative for Alzheimer's disease.

Vitis vinifera acts as anti-Alzheimer's agent by modulating biochemical parameters implicated in cognition and memory.

BACKGROUND: Aluminum a known neuro and cholinotoxin has been implicated in the pathogenesis of Alzheimer's disease. Its exposure is associated with impairment of the memory and cognition. OBJECTIVE: The present study was undertaken to evaluate the anti-Alzheimer's activity of Vitis vinifera in aluminum induced Alzheimer's disease. MATERIALS AND METHODS: In this study, we investigated the behavioral and biochemical effects of aluminum in Sprague-Dawley rats. Animals were exposed to aluminum chloride (100 mg/kg/day) orally for a period of 8 weeks. Vitis was given in doses of 250 mg/kg and 500 mg/kg for 16 weeks and the possible effects of Vitis vinifera on the expression of Tau and amyloid precursor protein were evaluated by PCR analysis and the possible activities of lipid peroxidation, inflammation and anti-cholinesterase activity were evaluated. RESULTS: Aluminum intoxication was associated with significant impairment in learning and memory in Morris water maze test. A significant improvement was observed with Vitis vinifera in a dose dependent manner. CONCLUSION: The findings of the present study revealed the significant neuroprotective actions of Vitis vinifera by modifying the biochemical parameters and inhibited the mRNA expression of Amyloid Precursor Protein and Tau, which are the key pathological hallmarks of Alzheimer's disease, which was further confirmed by histopathological observations.

Cerebroprotective Actions of Triticum aestivum Linn Powder and Bauhinia purpurea Flower Powder in Surgically Induced Cerebral Infraction in Rats.

OBJECTIVE: The prime objective of this study is to evaluate the cerebroprotective actions of Triticum aestivum (wheatgrass) powder and Bauhinia purpurea flower (dev kanchan) powder against the experimentally induced global ischemia reperfusion injury in rats. MATERIALS AND METHODS: In the first phase of the studies, 1 h before the surgical procedure, the Wistar rats were orally served with varied doses of wheatgrass powder (5, 10, 30, and 100 µg/kg) and Bauhinia flower powder (30, 100, 200, and 300 µg/kg), respectively. The ischemia was induced by 30-min bilateral carotid artery occlusion in succession to reperfusion for 4 h. It was proved that the wheatgrass powder and Bauhinia flower powder yielded a significant, dose-dependent cerebroprotection in terms of reduction in cerebral infarct size when compared with the control group. Coming to the second phase of the studies, a certain potential dose of 10 µg/kg of wheatgrass and 200 µg/kg of Bauhinia flower powders was selected keeping the protective action in view, and the animals were treated for 15 days. RESULTS: The major findings of the study are that wheatgrass and Bauhinia flower powders significantly augmented the magnitude of the antioxidant enzymes, viz., super oxide dismutase and catalase, and further reduced the levels of lipid peroxidation. CONCLUSIONS: The present study clearly showed that the wheatgrass powder and Bauhinia flower powder possess significant antioxidant properties that may act as a key ingredient in various ayurvedic preparations for the treatment of various diseases like cerebral ischemic reperfusion injury. SUMMARY: The wheat grass contains high amount of bioflavonoids, alkaloids, SOD etc which are responsible for anti oxidant activity.The Bauhinia purpurea contains glycosides, flavonoids and also plays a major role in DPPH activity which is responsible for anti oxidant activity.The wheat grass (10 mg/kg) and bauhinia (200 mg/kg) significantly(P < 0.0001) reduced the percentage of infract size when compared to Ischemia reperfusion control group.The wheat grass (10 mg/kg) and bauhinia (200 mg/kg) significantly (P <0.0001) reduced the lipid peroxidation (MDA) and increased SOD and Catalase. Abbreviations used: BCAO: Bilateral Carotid Artery Occlusion, MCA: middle cerebral artery, ROS: reactive oxygen species, SCMC: Sodium carboxy methyl cellulose, p.o: Per oral route, T.T.C: Triphenyl tetrazolium chloride, MDA: Malondialdehyde, SOD: Super oxide dismutase.

Prediabetes and Alzheimer's Disease.

Aging patients with diabetes are at higher risk of developing Alzheimer's disease. Emerging evidences demonstrate the role of brain insulin resistance, which is a key mediator in prediabetes and diabetes mellitus that may lead to Alzheimer's disease. Insulin and insulin-like growth factors regulate many biological processes such as axonal growth, protein synthesis, cell growth, gene expression, proliferation, differentiation, and development. Among these, the energy metabolism and synaptic plasticity are the major transduction processes regulated by insulin, which are the core objectives for learning and memory. It was also proposed that hyper insulinemia induced insulin resistance results in injury to the central nervous system by the activation of glycogen synthase kinase 3ß which is the key ailment in the cognitive decline. Hence, the endogenous brain specific insulin impairments and signaling account for the majority of Alzheimer's abnormalities.

Effect of wheat grass powder on aluminum induced Alzheimer's disease in Wistar rats.

OBJECTIVE: To find out the effect of wheat grass on aluminum induced Alzheimer's disease in Wistar rats. METHODS: Memory impairment was induced by aluminum chloride (4.2 mg/kg, i.p.) for 28 d. Memory function was assessed by Morris water maze test. To study the activity of wheat grass (100 mg/kg, p.o.), Wistar rats were administered it for 28 d along with aluminum chloride. Biochemical parameters of oxidative stress were estimated in brain after the treatment. RESULTS: The major finding of this study is that aluminum enhanced oxidative stress. Wheat grass showed a significant improvement in reduction of this oxidative stress by reduction of malondialdehyde levels and enhancement of superoxide dismutase and catalase levels. CONCLUSIONS: The present study clearly demonstrated the beneficial effects of wheat grass that shows good antioxidant properties, and this remarkable effect of wheat grass may act as a key to treat Alzheimer's disease.