Alzheimer Disease: Streit WJ

Streit WJ, Miller KR, Lopes KO, Njie E. · Department of Neuroscience, University of Florida, Gainesville, FL 32610, USA. · Front Biosci. · Pubmed #18508444 No free full text.

Abstract: We have long promulgated the idea that microglial cells serve an entirely beneficial role in the central nervous system (CNS), not only as immunological sentinels to fend off potentially dangerous infections, but also as constitutively neuroprotective glia that help sustain neuronal function in the normal and especially in the injured CNS when microglia become activated. In recent years, we have reported on the presence of degenerating microglial cells, which are prominent in the brains of aged humans and humans with neurodegenerative diseases, and this has led us to propose a hypothesis stating that loss of microglia and microglial neuroprotective functions could, at least in part, account for aging-related neurodegeneration. In the current review, we sum up the many aspects that characterize microglial activation and compare them to those that characterize microglial senescence and degeneration. We also consider the possible role of oxidative stress as a cause of microglial degeneration. We finish up by discussing the role microglial cells play in terms of amyloid clearance and degradation with the underlying idea that removal of amyloid constitutes a microglial neuroprotective function, which may become compromised during aging.

Streit WJ, Conde JR, Fendrick SE, Flanary BE, Mariani CL. · Department of Neuroscience, University of Florida College of Medicine and McKnight Brain Institute, Gainesville, FL 32610, USA. · Neurol Res. · Pubmed #16197805 No free full text.

Abstract: Microglial cells comprise a network of endogenous immunocompetent cells that pervade the brain and spinal cord. The primary function of this system is to provide continuous surveillance of the parenchyma and protect the central nervous system (CNS) during injury and disease. Here we discuss the involvement of microglia during brain aging and aging-related neurodegenerative disease, i.e. Alzheimer's disease, and briefly summarize their possible roles in amyotrophic lateral sclerosis (ALS). In addition, we provide an overview of the neuroinflammation associated with primary brain tumors and how microglial tumor cytotoxicity could be targeted for immunotherapeutic approaches designed to treat these lesions.

Streit WJ. · Department of Neuroscience, University of Florida College of Medicine, Gainesville, 32610-0244, USA. · Brain Res Brain Res Rev. · Pubmed #15850662 No free full text.

Abstract: The first part of this paper summarizes some of the key observations from experimental work in animals that support a role of microglia as neuroprotective cells after acute neuronal injury. These studies point towards an important role of neuronal-microglial crosstalk in the facilitation of neuroprotection. Conceptually, injured neurons are thought to generate rescue signals that trigger microglial activation and, in turn, activated microglia produce trophic or other factors that help damaged neurons recover from injury. Against this background, the second part of this paper summarizes recent work from postmortem studies conducted in humans that have revealed the occurrence of senescent, or dystrophic, microglial cells in the aged and Alzheimer's disease brain. These findings suggest that microglial cells become increasingly dysfunctional with advancing age and that a loss of microglial cell function may involve a loss of neuroprotective properties that could contribute to the development of aging-related neurodegeneration.

Streit WJ. · Department of Neuroscience, University of Florida College of Medicine, Gainesville, Florida 32610-0244, USA. · J Neurosci Res. · Pubmed #15197750 No free full text.

Abstract: The most visible and, until very recently, the only hypothesis regarding the involvement of microglial cells in Alzheimer's disease (AD) pathogenesis is centered around the notion that activated microglia are neurotoxin-producing immune effector cells actively involved in causing the neurodegeneration that is the cause for AD dementia. The concept of detrimental neuroinflammation has gained a strong foothold in the AD arena and is being expanded to other neurodegenerative diseases. This review takes a comprehensive and critical look at the overall evidence supporting the neuroinflammation hypothesis and points out some weaknesses. The current work also reviews evidence for an alternative theory, the microglial dysfunction hypothesis, which, although eliminating some of the shortcomings, does not necessarily negate the amyloid/neuroinflammation theory. The microglial dysfunction theory offers a different perspective on the identity of activated microglia and their role in AD pathogenesis taking into account the most recent insights gained from studying basic microglial biology.

Streit WJ. · Department of Neuroscience, P.O. Box 100244, Building 59, University of Florida, College of Medicine, 100 Newell Drive, Gainesville, FL 32611, USA. · Ernst Schering Res Found Workshop. · Pubmed #12066409 No free full text.

This publication has no abstract.

Streit WJ, Conde JR, Harrison JK. · Department of Neuroscience, University of Florida College of Medicine and McKnight Brain Institute, Gainesville, FL 32611, USA. · Neurobiol Aging. · Pubmed #11754998 No free full text.

Abstract: In recent years, increasing attention has been focused on chemokines as inflammatory mediators in the CNS. The limited number of studies that have investigated chemokine and chemokine receptor expression in Alzheimer's disease (AD) brain and in cell culture models seem to support a role for inflammation in AD pathogenesis. Here we provide a review of these studies, but in addition, point out the possible role of chemokines as communication molecules between neurons and microglia. Understanding neuron-microglia interactions is essential for understanding AD pathogenesis, and disturbances in chemokine-mediated intercellular communication may contribute toward a generalized impairment of microglial cell function.

Lopes KO, Sparks DL, Streit WJ. · Department of Neuroscience, University of Florida College of Medicine, Gainesville, Florida 32610-0244, USA. · Glia. · Pubmed #18442088 No free full text.

Abstract: Degeneration of microglial cells may be important for understanding the pathogenesis of aging-related neurodegeneration and neurodegenerative diseases. In this study, we analyzed the morphological characteristics of microglial cells in the nondemented and Alzheimer's disease (AD) human brain using ferritin immunohistochemistry. The central hypothesis was that expression of the iron storage protein ferritin increases the susceptibility of microglia to degeneration, particularly in the aged brain since senescent microglia might become less efficient in maintaining iron homeostasis and free iron can promote oxidative damage. In a primary set of 24 subjects (age range 34-97 years) examined, microglial cells immunoreactive for ferritin were found to constitute a subpopulation of the larger microglial pool labeled with an antibody for HLA-DR antigens. The majority of these ferritin-positive microglia exhibited aberrant morphological (dystrophic) changes in the aged and particularly in the AD brain. No spatial correlation was found between ferritin-positive dystrophic microglia and senile plaques in AD tissues. Analysis of a secondary set of human postmortem brain tissues with a wide range of postmortem intervals (PMI, average 10.94 +/- 5.69 h) showed that the occurrence of microglial dystrophy was independent of PMI and consequently not a product of tissue autolysis. Collectively, these results suggest that microglial involvement in iron storage and metabolism contributes to their degeneration, possibly through increased exposure of the cells to oxidative stress. We conclude that ferritin immunohistochemistry may be a useful method for detecting degenerating microglia in the human brain.

Flanary BE, Sammons NW, Nguyen C, Walker D, Streit WJ. · Department of Neuroscience, University of Florida College of Medicine, McKnight Brain Institute, Gainesville, Florida 32610-0244, USA. · Rejuvenation Res. · Pubmed #17378753 No free full text.

Abstract: Advanced age and presence of intracerebral amyloid deposits are known to be major risk factors for development of neurodegeneration in Alzheimer's disease (AD), and both have been associated with microglial activation. However, the specific role of activated microglia in AD pathogenesis remains unresolved. Here we report that microglial cells exhibit significant telomere shortening and reduction of telomerase activity with normal aging in rats, and that in humans there is a tendency toward telomere shortening with presence of dementia. Human brains containing high amyloid loads demonstrate a significantly higher degree of microglial dystrophy than nondemented, amyloid-free control subjects. Collectively, these findings show that microglial cell senescence associated with telomere shortening and normal aging is exacerbated by the presence of amyloid. They suggest that degeneration of microglia is a factor in the pathogenesis of AD.

Collingwood JF, Mikhaylova A, Davidson M, Batich C, Streit WJ, Terry J, Dobson J. · Institute for Science & Technology in Medicine, Keele University, Thornburrow Drive, Hartshill, Stoke-on-Trent, ST4 7QB United Kingdom. · J Alzheimers Dis. · Pubmed #16131727 No free full text.

Abstract: There is a well-established link between iron overload in the brain and pathology associated with neurodegeneration in a variety of disorders such as Alzheimer's (AD), Parkinson's (PD) and Huntington's (HD) diseases [1]. This association was first discovered in AD by Goodman in 1953 [2], where, in addition to abnormally high concentrations of iron in autopsy brain tissue, iron has also been shown to accumulate at sites of brain pathology such as senile plaques [3]. However, since this discovery, progress in understanding the origin, role and nature of iron compounds associated with neurodegeneration has been slow. Here we report, for the first time, the location and characterisation of iron compounds in human AD brain tissue sections. Iron fluorescence was mapped over a frontal-lobe tissue section from an Alzheimer's patient, and anomalous iron concentrations were identified using synchrotron X-ray absorption techniques at 5 mum spatial resolution. Concentrations of ferritin and magnetite, a magnetic iron oxide potentially indicating disrupted brain-iron metabolism, were evident. These results demonstrate a practical means of correlating iron compounds and disease pathology in-situ and have clear implications for disease pathogenesis and potential therapies.