Oxidative Stress and Metabolic Syndrome: Cause or Consequence of Alzheimer's Disease?

Alzheimer’s disease (AD) is a major neurodegenerative disease affecting the elderly. Clinically, it is characterized by a progressive loss of memory and cognitive function. Neuropathologically, it is characterized by the presence of extracellular β-amyloid (Aβ) deposited as neuritic plaques (NP) and neurofibrillary tangles (NFT) made of abnormal and hyperphosphorylated tau protein. These lesions are capable of generating the neuronal damage that leads to cell death and cognitive failure through the generation of reactive oxygen species (ROS). Evidence indicates the critical role of Aβ metabolism in prompting the oxidative stress observed in AD patients. However, it has also been proposed that oxidative damage precedes the onset of clinical and pathological AD symptoms, including amyloid-β deposition, neurofibrillary tangle formation, vascular malfunction, metabolic syndrome, and cognitive decline. This paper provides a brief description of the three main proteins associated with the development of the disease (Aβ, tau, and ApoE) and describes their role in the generation of oxidative stress. Finally, we describe the mitochondrial alterations that are generated by Aβ and examine the relationship of vascular damage which is a potential prognostic tool of metabolic syndrome. In addition, new therapeutic approaches targeting ROS sources and metabolic support were reported

Microglial motility and morphology in Alzheimer's Disease, and after Aβ42- immunotherapy

Microglia are the resident immune cells of the brain. Their main functions in the adult brain are to provide protection against pathogens and to remove cellular debris via phagocytosis. Microglial function is highly dependent on cell motility. Evidence from Alzheimer’s disease (AD) animal models supports microglial motility impairment in AD, possibly linked to Aβ accumulation. In AD patients immunised against Aβ42, Aβ plaque removal is partly due to phagocytic microglia, supporting an association between microglial function and Aβ clearance. The aim of the present study is to evaluate the expression of microglial motility-related proteins, as well as microglial morphological features, in the inferior parietal lobule of 32 controls, 44 AD cases and 16 immunised AD (iAD) cases, patients who had been immunised against the Aβ42 peptide. Immunohistochemistry (IHC) was performed for the proteins Iba1, CFL1, CORO1A and P2RY12, and protein load was assessed with an automated image analysis method. The neuroinflammatory environment was evaluated with Meso Scale Discovery protein immunoassays. Iba1 IHC was also used for microglial cell counting and morphological analysis. Fluorescent Iba1 IHC, confocal microscopy and semi-automated 3Dreconstruction were used for detailed assessment of microglial morphological features. Among the most relevant results, the levels of the motility-related proteins studied showed no difference in AD cases compared to controls. In the iAD group compared to AD, the levels of Iba1 were increased in grey and white matter, and the level of P2RY12 in the grey matter only.There was no difference in the total number of microglia in AD compared to controls, but there was an increase in iAD compared to AD. The ramified population was reduced in AD compared to controls, while in iAD both the ramified and amoeboid populations were increased. The microglial cell body volume was increased in AD compared to controls, whereas the total process length was increased in iAD compared to AD. Our results highlight some potentially relevant effects of the disease, and of Aβimmunotherapy on microglial motility, and help further our understanding of the functional spectrum of microglia in health and disease

Dataset for: Load of motility-related microglial proteins, inflammation-related proteins, and microglial morphological features in controls, Alzheimer's Disease (AD) cases, and AD cases after Aβ42-immunotherapy

Data underpinning the findings of the PhD thesis &quot;Microglial motility and morphology in AD and after amyloid-beta-42-immunotherapy&quot; </span

Molecular mechanisms of microglial motility: changes in ageing and Alzheimer’s disease

Microglia are the tissue-resident immune cells of the central nervous system, where they constitute the first line of defense against any pathogens or injury. Microglia are highly motile cells and in order to carry out their function, they constantly undergo changes in their morphology to adapt to their environment. The microglial motility and morphological versatility are the result of a complex molecular machinery, mainly composed of mechanisms of organization of the actin cytoskeleton, coupled with a “sensory” system of membrane receptors that allow the cells to perceive changes in their microenvironment and modulate their responses. Evidence points to microglia as accountable for some of the changes observed in the brain during ageing, and microglia have a role in the development of neurodegenerative diseases, such as Alzheimer’s disease. The present review describes in detail the main mechanisms driving microglial motility in physiological conditions, namely, the cytoskeletal actin dynamics, with emphasis in proteins highly expressed in microglia, and the role of chemotactic membrane proteins, such as the fractalkine and purinergic receptors. The review further delves into the changes occurring to the involved proteins and pathways specifically during ageing and in Alzheimer’s disease, analyzing how these changes might participate in the development of this disease

Innate immunity in Alzheimer's disease: the relevance of animal models?

The mouse is one of the organisms most widely used as an animal model in biomedical research, due to the particular ease with which it can be handled and reproduced in laboratory. As a member of the mammalian class, mice share with humans many features regarding metabolic pathways, cell morphology and anatomy. However, important biological differences between mice and humans exist and must be taken into consideration when interpreting research results, in order to properly translate evidence from experimental studies into information that can be useful for human disease prevention and/or treatment.With respect to Alzheimer’s disease (AD), much of the experimental information currently known about this disease has been gathered from studies using mainly mice as models. Therefore, it is notably important to fully characterise the differences between mice and humans regarding important aspects of the disease. It is now widely known that inflammation plays an important role in the development of AD, a role that is not only a response to the surrounding pathological environment, but rather seems to be strongly implicated in the aetiology of the disease as indicated by the genetic studies. This review highlights relevant differences in inflammation and in microglia, the innate immune cell of the brain, between mice and humans regarding genetics and morphology in normal ageing, and the relationship of microglia with AD-like pathology, the inflammatory profile and cognition.We conclude that, although there are some noteworthy differences exist between mice and humans regarding microglial characteristics, mainly in distribution, and gene expression and states of activation. This may have repercussions in the way transgenic mice respond to, and influence, the AD-like pathology. However, despite these differences, human and mouse microglia also show several similarities in activation patterns, morphology and behaviour such that the mouse is a suitable model for studying the role of microglia in Alzheimer’s disease and other neurodegenerative diseases, as long as these differences are taken into consideration when delineating new strategies to approach the study of neurodegenerative diseases

Innate immunity in Alzheimer's disease: the relevance of animal models?

The mouse is one of the organisms most widely used as an animal model in biomedical research, due to the particular ease with which it can be handled and reproduced in laboratory. As a member of the mammalian class, mice share with humans many features regarding metabolic pathways, cell morphology and anatomy. However, important biological differences between mice and humans exist and must be taken into consideration when interpreting research results, in order to properly translate evidence from experimental studies into information that can be useful for human disease prevention and/or treatment.With respect to Alzheimer’s disease (AD), much of the experimental information currently known about this disease has been gathered from studies using mainly mice as models. Therefore, it is notably important to fully characterise the differences between mice and humans regarding important aspects of the disease. It is now widely known that inflammation plays an important role in the development of AD, a role that is not only a response to the surrounding pathological environment, but rather seems to be strongly implicated in the aetiology of the disease as indicated by the genetic studies. This review highlights relevant differences in inflammation and in microglia, the innate immune cell of the brain, between mice and humans regarding genetics and morphology in normal ageing, and the relationship of microglia with AD-like pathology, the inflammatory profile and cognition.We conclude that, although there are some noteworthy differences exist between mice and humans regarding microglial characteristics, mainly in distribution, and gene expression and states of activation. This may have repercussions in the way transgenic mice respond to, and influence, the AD-like pathology. However, despite these differences, human and mouse microglia also show several similarities in activation patterns, morphology and behaviour such that the mouse is a suitable model for studying the role of microglia in Alzheimer’s disease and other neurodegenerative diseases, as long as these differences are taken into consideration when delineating new strategies to approach the study of neurodegenerative diseases

Early Onset Alzheimer’s Disease and Oxidative Stress

Alzheimer’s disease (AD) is the most common cause of dementia in elderly adults. It is estimated that 10% of the world’s population aged more than 60–65 years could currently be affected by AD, and that in the next 20 years, there could be more than 30 million people affected by this pathology. One of the great challenges in this regard is that AD is not just a scientific problem; it is associated with major psychosocial and ethical dilemmas and has a negative impact on national economies. The neurodegenerative process that occurs in AD involves a specific nervous cell dysfunction, which leads to neuronal death. Mutations in APP, PS1, and PS2 genes are causes for early onset AD. Several animal models have demonstrated that alterations in these proteins are able to induce oxidative damage, which in turn favors the development of AD. This paper provides a review of many, although not all, of the mutations present in patients with familial Alzheimer’s disease and the association between some of these mutations with both oxidative damage and the development of the pathology

Microglial motility in Alzheimer’s disease and after Aβ42 immunotherapy: a human post-mortem study

Microglial function is highly dependent on cell motility, with baseline motility required for homeostatic surveillance activity and directed motility to migrate towards a source of injury. Experimental evidence suggests impaired microglial motility in Alzheimer’s disease (AD) and therefore we have investigated whether the expression of proteins associated with motility is altered in AD and affected by the Aβ immunotherapy using post-mortem brain tissue of 32 controls, 44 AD cases, and 16 AD cases from our unique group of patients immunised against Aβ42 (iAD). Sections of brain were immunolabelled and quantified for (i) the motility-related microglial proteins Iba1, cofilin 1 (CFL1), coronin-1a (CORO1A) and P2RY12, and (ii) pan-Aβ, Aβ42 and phosphorylated tau (ptau). The neuroinflammatory environment was characterised using Meso Scale Discovery multiplex assays. The expression of all four motility-related proteins was unmodified in AD compared with controls, whereas Iba1 and P2RY12, the homeostatic markers, were increased in the iAD group compared with AD. Iba1 and P2RY12 showed significant positive correlations with Aβ in controls but not in the AD or iAD groups. Pro- and anti-inflammatory proteins were increased in AD, whereas immunotherapy appears to result in a slightly less pro-inflammatory environment. Our findings suggest that as Aβ appears during the ageing process, the homeostatic Iba1 and P2RY12 –positive microglia respond to Aβ, but this response is absent in AD. Aβ immunisation promoted increased Iba1 and P2RY12 expression, likely reflecting increased baseline microglial motility but without restoring the profile observed in control

Microglial morphology in Alzheimer's disease and after Aβ immunotherapy

Microglia are the brain immune cells and their function is highly dependent on cell motility. It was hypothesised that morphological variability leads to differences in motility, ultimately impacting on the microglial function. Here, we assessed microglial morphology in 32 controls, 44 Alzheimer's disease (AD) cases and 16 AD cases from patients immunised against Aβ42 (iAD) using 2D and 3D approaches. Our 2D assessment showed an increased number of microglia in iAD vs. AD (P = 0.032) and controls (P = 0.018). Ramified microglia were fewer in AD vs. controls (P = 0.041) but increased in iAD compared to AD (P &lt; 0.001) and controls (P = 0.006). 3D reconstructions highlighted larger cell bodies in AD vs. controls (P = 0.049) and increased total process length in iAD vs. AD (P = 0.032), with negative correlations detected for pan-Aβ load with total process length (P &lt; 0.001) in AD and number of primary processes (P = 0.043) in iAD. In summary, reactive/amoeboid microglia are the most represented population in the aged human brain. AD does not affect the number of microglia, but the ramified population is decreased adopting a more reactive morphology. Aβ removal by immunotherapy leads to increased ramified microglia, implying that the cells retain plasticity in an aged disease brain meriting further investigation.</p