Current Alzheimer Research - Volume 14, Issue 1, 2017

Background: Alzheimer's disease (AD) develops undetected for years due to the lack of early diagnostic biomarkers. In advanced AD, visual deficits related to cortical neurodegeneration are well recognized, but recent studies have identified that the retina could be affected prior to vulnerable brain areas such as cortex and hippocampus. In this review, we discuss a new evidence suggesting that functional alterations in the retina may become the earliest diagnostic biomarkers for AD. Methods: Analytical analysis of bibliographic databases for peer-reviewed research literature was performed by focusing on the review topic and using standard inclusion/exclusion criteria in the context of the given conceptual framework i.e., that synaptic dysfunction within the retina may be reminiscent of changes within the brain. Results: A total of 134 papers were included in the review, the majority (52) dealing with the earliest dysfunction of synaptic and neuronal networks in vulnerable brain areas to point out how they may inspire the analogous research in the retina. The general aspects of retina organization and the retinal alterations in the late stages of AD are then discussed based on the analysis of the next 40 and 31 papers, respectively. We finally present evidence (11 papers) indicating why putative retinal synaptic dysfunction holds the potential to become the earliest sign of AD, allowing for a non-invasive and easy detection using modern imaging and functional techniques. Conclusion: Translation of these findings to clinical diagnosis could lead to earlier therapeutic interventions and, consequently, better chances to delay or halt AD progression.

Background: Alzheimer's disease (AD) is characterized by accumulation and aggregation of beta-amyloid peptide, neurofibrillary tangles of hyperphosphorylated tau, neuroinflammation, synaptic degeneration and eventual neuronal cell loss. Current treatment options for AD provide temporary symptomatic relief in a subset of patients. These drugs include cholinesterase inhibitors that improve cholinergic innervation such as rivastigmine, donepezil and galatamine. In addition, memantine, a Nmethyl- D-aspartate antagonist, is used to treat moderate to severe AD by reducing excitotoxicity. It has been proposed that increased excitation and decreased inhibition lead to aberrant excitatory neuronal activity and cognitive deficits in AD. Methods: We undertook a search of the literature using bibliographic databases to identify publications that were related to neuronal activity in Alzheimer's disease. We further delineated the publications to determine inclusion/exclusion criteria based on relevance to increased excitation or decreased inhibition of neuronal networks in both human patients and rodent models. The final criteria related to the potential use of α-Melanocyte stimulating hormone (α-MSH) as a potential treatment strategy for Alzheimer's disease. These data were utilized to obtain the content of this review. Results: We identified 156 peer-reviewed publications that met our criteria and describe the findings here. Rodent models of AD and ageing both exhibit cognitive deficits and loss of inhibitory GABAerigc interneurons. α-Melanocyte stimulating hormone is a neuropeptide that is down-regulated in the brain and cerebrospinal fluid of AD patients. α-MSH has many functions in the central nervous system including neuroprotective and anti-inflammatory effects that target multiple aspects of the AD pathology. α-MSH treatment promoted the survival of GABAergic interneurons in the hippocampus and improved spatial memory as well as alterations in anxiety in a mouse model of AD. The somatostatin expressing subpopulation of GABAergic interneurons are particularly preserved by α-MSH treatment. Somatostatin has been implicated in hippocampal-dependent cognitive tasks. Somatostatin-expressing interneurons have also been shown to play an important role in maintaining excitatory-inhibitory balance. α-MSH preserved GABAergic interneurons and by preventing the loss of the somatostatin subpopulation, it improved cognitive function. Conclusion: α-MSH is a novel candidate for the treatment of AD but its therapeutic potential in AD patients remains to be investigated.

Background: The early phase of Alzheimer's disease (AD) involves the disruption of finely tuned neuronal circuitry in brain regions associated with learning and memory. This tuning is obtained from the delicate balance of excitatory and inhibitory inputs which regulate cortical network function. This homeostatic plasticity provides a dynamic basis for appropriate information transfer in the brain. Excitatory synaptic transmission is driven mainly by glutamatergic synapses whereas inhibitory synaptic transmission involves GABAergic and glycinergic signaling. GABAergic cells, responsible for inhibitory transmission in adult brain, have recently become the subject of study in AD research. The discovery that GABAergic interneurons are targets of the amyloid-beta (Aβ) peptide suggest that deregulation of the excitatory/inhibitory balance contributes to changes in cortical regulation, possibly with consequences for the development of the pathology. Thus, understanding the molecular details involved in GABAergic alterations may provide insight into the pathogenesis of AD. Objective: Here, we review recent discoveries illustrating the concept of early alterations to the inhibitory circuits in AD and consider their functional implications for GABAergic components at membrane, cellular and microcircuit levels. Conclusion: We look at approaches that may lead to new hypotheses, animal models and therapeutic strategies based on GABAergic cells in AD with particular interest in microcircuits.

Background: The last two decades have seen a great advance in the data that supports the two current hypotheses in Alzheimer's disease field, the amyloid beta hypothesis and the tau hypothesis. Not surprisingly, Aβ and tau proteins are currently the major therapeutic research targets for AD treatment. Unfortunately, nothing but moderate success has emerged from such therapeutic approaches. With this in mind, we will discuss deep brain stimulation as a promising therapeutic strategy that aims to restore brain activity. Lastly, in the scope of cognitive deficit restoration, we will discuss the relevance of the limbic formation as a promising neuroanatomical target for deep brain stimulation. Methods: Immunohistochemistry for modified tau (phosphorylated at Ser199–202–Thr205 labelled by the antibody AT8) was performed on paraffin-embedded human brain sections providing a detailed characterization of NFT pathology. Results: Abnormally phosphorylated tau protein is the key common marker in several brain diseases such as Alzheimer's disease, Parkinson's disease, Pick Disease, Down syndrome and frontotemporal dementia and is capable of affecting synaptic events that are critical for memory formation. With this in mind, therapeutic strategies aiming to restore synaptic events could offer better outcomes. Conclusion: The humble success of current therapeutic strategies along with the lack of basic knowledge of the brain disease mechanisms calls for alternatives that benefit patients in the present moment. One of particular interest is the neurostimulation strategy that is already a well-established treatment for several movement disorders and when compared to current Alzheimer's therapeutic strategies, deep brain stimulation does not directly interfere with the normal protein function, therefore increasing the probability of success.

Background: Alzheimer's disease (AD) is characterized by neuronal degeneration, vascular pathology and cognitive decline. Furthermore, deficits in cerebral glucose metabolism and insulin resistance are being increasingly recognized in AD. Many lifestyle-modifying approaches, including diet and exercise, have yielded promising results in modulating brain morphology and function for the prevention and early treatment of AD. Objective: This review focuses on the effects of physical exercise on rescuing cognition and limiting the progression of AD pathology. Specifically, the impact of exercise, in human and animal models of AD, on the stimulation and preservation of cognition, neurotransmission, neurogenesis, vasculature, glucose metabolism and insulin signaling is discussed. Conclusion: Studies have highlighted the potential of physical activity to improve overall brain health, which could delay or lessen AD-related cognitive deficits and pathology. Physical activity influences cognitive function, vascular health and brain metabolism, which taken together offers benefits for the aging population, including AD patients.

Background: Behavioral and psychological symptoms of dementia (BPSD) associated with Alzheimer's Disease (AD) have been linked to structural and functional alterations in fronto-temporal circuits and cortical abnormalities. However, little is known on how specific volumetric and functional brain changes may be associated with the frequency, severity and pattern of BPSD. Methods: A systematic review of the literature regarding neuroimaging and BPSD changes in AD was performed through Pubmed/Medline, ISI, and EMBASE electronic databases from January 2000 to May 2015. Eligible references (n=40) included clinical studies in which structural or functional neuroimaging assessment was performed in AD subjects presenting BPSD features. Results: BPSD symptoms, particularly apathy and psychosis have been associated in most of studies with either volume reductions or decreased metabolism in the prefrontal cortex (orbital and dorsolateral portions), anterior cingulate, insula and temporal lobes (middle portion). WM lacunes associated with AD progression have been associated with depressive symptoms. Conclusion: The sum of evidence highlights the importance of BPSD-related imaging findings for the understanding of the non-cognitive symptom spectrum in AD. Results suggest that structural and functional changes in fronto-limbic areas may lead to emotional deregulation and symptom unawareness. As these findings may be present early on the AD clinical course, they may have a relevance for the development of imaging markers that could be used in diagnosis, disease monitoring and prediction of therapeutic response.

Background: Alzheimer's disease (AD) is a progressive neurodegenerative disease affecting elderly individuals at an alarming rate. It has become a global health crisis imposing tremendous social and economic burden on society. Although there is no cure for AD, it is important to identify and implement preventive strategies that may delay or prevent the symptoms, limit the burden, and improve the quality of life of those afflicted. Adequate nutrition and physical activity are the two potential lifestyle modifiable factors that have gained considerable interest for their potential in the prevention or management of this challenging disease. In this review, we discuss the beneficial effects of physical activity and adequate nutrition on minimizing the risk of developing AD. Methods: The research question was initially formulated in a structured and explicit way. Relevant studies were identified using a wide range of scientific databases. Their potential relevance was based on the criteria for inclusion and exclusion. The quality of selected studies was subjected to a more precise quality assessment using standard tools. A detailed description of the implemented intervention and how it differed from what the control group received was outlined. The effects of intervention on measurable outcomes for the study sample were applied. Results: One hundred and sixty-four references were included in the review comprising of epidemiological, longitudinal, cross-sectional, intervention and randomized controlled studies. This review highlighted the effect of various nutrient diet supplements on cognitive performance in humans as well as animals with AD and mild cognitive impairment (MCI). Moreover, the effect of physical exercise on the cognitive function in animal models with AD was outlined. Conclusion: The findings of this review highlight the therapeutic potential of combination of nutritionally adequate diet and physical activity in preventing or delaying the symptoms associated with AD pathology.

Background: Cholinergic cell loss in the basal forebrain, the major source of hippocampal cholinergic projections, has been implicated in Alzheimer's disease. Objective: To examine whether the septohippocampal pathway is involved in tauopathy model mice and to elucidate the tau-associated mechanism underlying cholinergic alteration. Methods: Adult (6 to 8 months old) and old (16 to 18 months old) transgenic mice expressing wild-type human tau, Tg601, were examined using Ex vivo diffusion tensor magnetic resonance imaging (DTI) and 2-[18F]fluoro- 2-deoxy-D-glucose positron emission tomography (FDG-PET). Choline acetyltransferase (ChAT)-positive neurons in the medial septum (MS) were counted by stereological methods. Acetylcholinesterase (AChE) activity and AChE mRNA in 6 brain regions were measured. Results: Ex vivo DTI revealed that the number of fractional anisotropy (FA) streamlines in the septohippocampal tract decreased with age in Tg601 mice. The FA value in the septum was lower in old Tg601 mice than in non-tg mice. A voxel-based statistical analysis of FDG-PET revealed the presence of low glucose uptake areas, involving the MS in adults, and spread over regions including the hippocampal dentate gyrus in old mice. In the MS, the number of choline acetyltransferase (ChAT)-positive neurons decreased in old Tg601 mice. AChE activity and AChE mRNA T transcripts were exclusively higher in the septum. Conclusion: The upregulation of AChE in the septum may result in the selective degeneration of the septohippocampal cholinergic pathway in the tauopathy mouse model.

Introduction: Alzheimer's disease (AD) is the most common cause of dementia. The search for new treatments is made more urgent given its increasing prevalence resulting from the aging of the global population. Over the past 20 years, stem cell technologies have become an increasingly attractive option to both study and potentially treat neurodegenerative diseases. Several investigators reported a beneficial effect of different types of stem or progenitor cells on the pathology and cognitive function in AD models. Mouse models are one of the most important research tools for finding new treatment for AD. We aimed to explore the possible therapeutic potential of human umbilical cord mesenchymal stem cell xenografts in a transgenic (Tg) mouse model of AD. Methods: APP/PS1 Tg AD model mice received human umbilical cord stem cells, directly injected into the carotid artery. To test the efficacy of the umbilical cord stem cells in this AD model, behavioral tasks (sensorimotor and cognitive tests) and immunohistochemical quantitation of the pathology was performed. Results: Treatment of the APP/PS1 AD model mice, with human umbilical cord stem cells, produced a reduction of the amyloid beta burden in the cortex and the hippocampus which correlated with a reduction of the cognitive loss. Conclusion: Human umbilical cord mesenchymal stem cells appear to reduce AD pathology in a transgenic mouse model as documented by a reduction of the amyloid plaque burden compared to controls. This amelioration of pathology correlates with improvements on cognitive and sensorimotor tasks.

Background: Many studies suggest oxidative stress as an early feature of Alzheimer’s Disease (AD). However, evidence of established oxidative stress in AD peripheral cells is still inconclusive, possibly due to both, differences in the type of samples and the heterogeneity of oxidative markers used in different studies. Objective: The aim of this study was to evaluate blood-based redox alterations in Alzheimer’s Disease in order to identify a peculiar disease profile. Method: To that purpose, we measured the activity of Superoxide Dismutase, Catalase and Glutathione Peroxidase both in the extracellular and the intracellular blood compartments of AD, MCI and control subjects. The amount of an open isoform of p53 protein (unfolded p53), resulting from oxidative modifications was also determined. Results: Decreased SOD, increased GPx activity and higher p53 open isoform were found in both AD and MCI plasma compared to controls. In blood peripheral mononuclear cells, SOD activity was also decreased in both AD and MCI, and unfolded p53 increased exquisitely in younger AD males compared to controls. Conclusion: Overall, these data highlight the importance of considering both extracellular and intracellular compartments, in the determination of antioxidant enzyme activities as well as specific oxidation end-products, in order to identify peculiar blood-based redox alterations in AD pathology.