Preclinical studies are essential for translation to disease treatments and effective use in clinical practice. An undue emphasis on single approaches to Alzheimer's disease (AD) appears to have retarded the pace of translation in the field, and there is much frustration in the public about the lack of an effective treatment. We critically reviewed past literature (1990-2014), analyzed numerous data, and discussed key issues at a consensus conference on Brain Ageing and Dementia to identify and overcome roadblocks in studies intended for translation. We highlight various factors that influence the translation of preclinical research and highlight specific preclinical strategies that have failed to demonstrate efficacy in clinical trials. The field has been hindered by the domination of the amyloid hypothesis in AD pathogenesis while the causative pathways in disease pathology are widely considered to be multifactorial. Understanding the causative events and mechanisms in the pathogenesis are equally important for translation. Greater efforts are necessary to fill in the gaps and overcome a variety of confounds in the generation, study design, testing, and evaluation of animal models and the application to future novel anti-dementia drug trials. A greater variety of potential disease mechanisms must be entertained to enhance progress.

It is well established that the regulation of epigenetic factors, including chromatic reorganization, histone modifications, DNA methylation, and miRNA regulation, is critical for the normal development and functioning of the human brain. There are a number of maternal factors influencing epigenetic pathways such as lifestyle, including diet, alcohol consumption, and smoking, as well as age and infections (viral or bacterial). Genetic and metabolic alterations such as obesity, gestational diabetes mellitus (GDM), and thyroidism alter epigenetic mechanisms, thereby contributing to neurodevelopmental disorders (NDs) such as embryonic neural tube defects (NTDs), autism, Down’s syndrome, Rett syndrome, and later onset of neuropsychological deficits. This review comprehensively describes the recent findings in the epigenetic landscape contributing to altered molecular profiles resulting in NDs. Furthermore, we will discuss potential avenues for future research to identify diagnostic markers and therapeutic epi-drugs to reverse these abnormalities in the brain as epigenetic marks are plastic and reversible in nature.

Alzheimer’s disease (AD) is one of the most common causes of dementia. Despite several decades of serious research in AD there is no standard disease modifying therapy available. Stem cells hold immense potential to regenerate tissue systems and are studied in a number of brain-related disorders. For various untreatable neurodegenerative disorders, such as Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS) and Parkinson’s disease (PD) (current-approved drugs provide only symptomatic relief), stem cell therapy holds a great promise and provides a great research opportunity. Here we review several stem cell transplantation studies with reference to both preclinical and clinical approaches. We focus on different sources of stem cells in a number of animal models and on molecular mechanisms involved in possible treatment of neurodegenerative disorders. The clinical studies reviewed suggest safety efficacy and translational potential of stem cell therapy. The therapeutic outcome of stem cell transplantation has been promising in many studies but no unifying hypothesis exists for an underlying mechanism. Some studies reported paracrine effects exerted by these cells via release of neurotrophic factors, while other studies reported immunomodulatory effects by transplanted cells. There are also reports supporting stem cell transplantation causing endogenous cell proliferation or replacement of diseased cells at the site of degeneration. In animal models of AD, stem cell transplantation is also believed to increase expression of synaptic proteins. A number of stem cell transplantation studies point out great potential for this novel approach in preventing or halting several neurodegenerative diseases. The current challenge is to clearly define the molecular mechanism by which stem cells operate and the extent of actual contribution by the exogenous and/or endogenous cells in the rescue of disease.

Dementia is a clinical syndrome with abnormal degree of memory loss and impaired ability to recall events from the past often characterized by Alzheimer's disease. The various strategies to treat dementia need validation of novel compounds in suitable animal models for testing their safety and efficacy. These may include novel anti-amnesic drugs derived from synthetic chemistry or those derived from traditional herbal sources. Multiple approaches have been adopted to create reliable animal models ranging from rodents to non-human primates, where the animals are exposed to a predetermined injury or causing genetic ablation across specific regions of brain suspected to affect learning functions. In this review various animal models for Alzheimer's disease and treatment strategies in development of anti dementia drugs are discussed and an attempt has been made to provide a comprehensive report of the latest developments in the field.

Prostaglandin-E 2 (PGE 2 ), an important mediator of inflammation, achieves its functions via four different G protein-coupled receptors (EP1, EP2, EP3, and EP4). We previously demonstrated that the EP2 receptor plays a proinflammatory and neurodegenerative role after status epilepticus (SE). We recently developed TG8-260 as a second-generation highly potent and selective EP2 antagonist. Here, we investigate whether TG8-260 is anti-inflammatory and combats neuropathology caused by pilocarpineinduced SE in rats. Adult male Sprague-Dawley rats were injected subcutaneously with pilocarpine (380-400 mg/kg) to induce SE. Following 60 min of SE, the rats were administered three doses of TG8-260 or vehicle and were allowed to recover. Neurodegeneration, neuroinflammation, gliosis, and blood-brain barrier (BBB) integrity were examined 4 days after SE. The results confirmed that pilocarpine-induced SE results in hippocampal neurodegeneration and a robust inflammatory response that persists days after SE. Furthermore, inhibition of the EP2 receptor by TG8-260 administered beginning 2 h after SE significantly reduced hippocampal neuroinflammation and gliosis but, in distinction to the earlier generation EP2 antagonist, did not mitigate neuronal injury or BBB breakdown. Thus, attenuation of neuroinflammation and gliosis is a common feature of EP2 inhibition following SE.