Inflammatory pathogenesis in Alzheimer's disease: biological mechanisms and cognitive sequeli

doi:10.1016/S0149-7634(98)00058-X

Neuroscience & Biobehavioral Reviews

Volume 23, Issue 5, May 1999, Pages 615-633

https://doi.org/10.1016/S0149-7634(98)00058-X Get rights and content

Abstract

Experimental evidence from molecular biology, biochemistry, epidemiology and behavioral research support the conclusion that brain inflammation contributes to the pathogenesis of Alzheimer’s disease and other types of human dementias. Aspects of neuroimmunology relating to the pathogenesis of Alzheimer’s disease are briefly reviewed. The effects of brain inflammation, mediated through cytokines and other secretory products of activated glial cells, on neurotransmission (specifically, nitric oxide, glutamate, and acetylcholine), amyloidogenesis, proteolysis, and oxidative stress are discussed within the context of the pathogenesis of learning and memory dysfunction in Alzheimer’s disease. Alzheimer’s disease is proposed to be an etiologically heterogeneous syndrome with the common elements of amyloid deposition and inflammatory neuronal damage.

Section snippets

Neuroimmunology of cognitive deficits in Alzheimer’s disease

Dysregulation of the normal processes of brain immunity has been implicated in the pathogenesis of numerous neuropsychological diseases, including Alzheimer’s disease [43], AIDS-related dementia [71], [76], [161], [171], [178], schizophrenia [69], [98], Multiple Sclerosis (MS) [69], [157], human prion diseases [127] and other human dementias. Immune-mediated neuronal damage may contribute to the pathogenesis of CNS diseases which, in contrast to autoimmune diseases such as MS, are not directly

Immune responsive cells in the brain: Astrocytes and microglia

Brain immunity is mediated predominantly by glial cells, particularly astrocytes (approximately 85% of glial cell population) and microglia (approximately 10% of glial cells). Immune activated glial cells produce a host of immune signaling and effector molecules, including proinflammatory and anti-inflammatory cytokines [17], chemotactic and cell adhesion molecules [24], [110], complement proteins [14], [29], [160], and cytotoxic free radicals [28], [78], and microglia also perform a phagocytic

Molecular mediators of brain inflammation: Cytokines

Cytokines are a class of polypeptides that are expressed at a low level in healthy tissue but can be induced rapidly in response to tissue trauma or immune challenge to serve a variety of immune signaling and effector functions. More than 40 different cytokines have been identified as well as numerous cytokine receptor types and subtypes [59], [71]. The conception of the functional role of cytokines has broadened as the characterization of the first cytokine, IL-1. Several authors have recently

Bi-directional peripheral-central immune signaling

Transmission of immune signals between the periphery and CNS may be a necessary event in the development of inflammatory brain damage in certain neurological disorders, including AIDS dementia, Multiple Sclerosis, and Alzheimer’s [52], [68], [77]. While the role of brain-peripheral immune system coordination in normal immunity or disease pathogenesis is not definitively known, experiments have demonstrated some of the biochemical mechanisms of immune signaling and have led to theories about

Immune-mediated Neuropathology in Alzheimer’s disease

In a review of a conference entitled, ‘Cytokines in the brain: Neuropathological Aspects,’ held in St.-Jean-de-Luz in April, 1996, the authors state, as a general theme of the research they review, that “cytokines contribute to most if not all acute and chronic CNS pathologies” [161]. Table 1 lists human neurological diseases along with recent references reporting evidence for immune pathogenesis. One of the key observations which suggests immune-mediated pathogenesis in a wide spectrum of

Mechanisms of inflammatory neurotoxicity and cognitive impairment: Modulation of neurotransmitter systems

Brain inflammation is associated with the synthesis and secretion, particularly from activated glial cells, of a number of neuroactive molecules, including cytokines, reactive oxygen- and nitrogen- free radicals, complement proteins, excitatory amino acids, Aβ, proteases and protease inhibitors [29], [81], [104], [166]. Among these, cytokines in particular are likely to contribute to the development of cognitive dysfunction given their ability to modulate neurotransmitter and second-messenger

Cytokines alter cognitive processes and behavior in humans and experimental animals: implications for Alzheimer’s disease

“[I]t is indisputable that the ultimate criterion of success or failure of any approach to treatment, including pharmacological, in Alzheimer’s or in other dementias must be behavioral. Therefore, effective research on the treatment of demented patients is dependent upon the existence of precise behavioral methods of assessing the effects of proposed new forms of treatment. Here, too, tools must be made available which are sufficiently sensitive to detect small but significant improvements in a

Conclusions and prospects for immune-based therapies

Oken [127] and others [161] have proposed immune-mediated neurotoxicity as “a unifying hypothesis of neurodegenerative diseases,” in the sense that neurodegenerative syndromes of diverse etiology may share the feature of inflammatory neuronal damage as the final pathway leading to clinical impairments. Three types of evidence supporting the role inflammatory processes in Alzheimer’s disease pathology have been reviewed; (1) the co-regulatory and neurotoxic interactions among Aβ, proteases and

Acknowledgements

We thank Dr. Shuxian Hu and Dr. Philip Peterson for supplying the photomicrograph images and for their help with the manuscript.

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Inflammatory pathogenesis in Alzheimer's disease: biological mechanisms and cognitive sequeli

Abstract

Section snippets

Neuroimmunology of cognitive deficits in Alzheimer’s disease

Immune responsive cells in the brain: Astrocytes and microglia

Molecular mediators of brain inflammation: Cytokines

Bi-directional peripheral-central immune signaling

Immune-mediated Neuropathology in Alzheimer’s disease

Mechanisms of inflammatory neurotoxicity and cognitive impairment: Modulation of neurotransmitter systems

Cytokines alter cognitive processes and behavior in humans and experimental animals: implications for Alzheimer’s disease

Conclusions and prospects for immune-based therapies

Acknowledgements

Brain Res

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Brain Beh Immun

Cytokine

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Inflammatory mechansims in Alzheimer’s disease: Implications for therapy

Am J Psychiatry

Alpha-secretase-derived product of beta-amyloid precursor protein is decreased by presenilin 1 mutations linked to familial Alzheimer’s disease

J Neurochem

Neurofibrillary tangles but not senile plaques parallel duration and severity of Alzheimer’s disease

Neurology

Muscarinic receptors mediating depression and long-term potentiation in rat hippocampus

J Physiol

Neuroinflammation destroys basal forebrain cholinergic neurons in a time dependent manner

Society for Neuroscience Abstracts

Passage of cytokines across the blood-brain barrier

Neuroimmunomodulation

Microglial activation by Alzheimer amyloid precursor protein and modulation by apolipoprotein E. Nature

Complement biosynthesis in the central nervous system

Crit Rev Oral Biol Med

Extracellular signal-regulated kinase and p38 subgroups of mitogen-activated protein kinases regulate inducible nitric oxide synthase and tumor necrosis factor-alpha gene expression in endotoxin-stimulated primary glial cultures

J Neurosci

Inverse association of anti-inflammatory treatments and Alzheimer’s disease: Initial results of a co-twin study

Neurology

Inflammatory processes induce β-Amyloid precursor protein changes in mouse brain

Proc the Natl Acad Sci USA