Insights into the neurodegenerative process of Alzheimer's disease: a role for mononuclear phagocyte-associated inflammation and neurotoxicity

Abstract

Since the first description of Alzheimer's disease (AD) in 1907, significant progress was made into understanding disease pathophysiology. The enormous effort in AD research has translated into the discovery of genetic linkages for disease, into elucidating the structure and function of the etiologic ␤-amyloid protein, and into unraveling the seemingly complex neuroimmunological cascade that affects neuronal dysfunction. Although effective therapies do not currently exist, many are being developed. We propose that the neuropathogenesis of AD, in measure, revolves around the immunological activation of glial cells, which in turn leads to alterations in inflammatory neurotoxin production, and ultimately to neuronal injury and death. Elucidating the mechanisms involved in such glial cell immune activation should provide valuable insights into understanding the disease process and in providing effective therapeutics to prevent and/or retard the devastating neurodegeneration that afflicts so many of our elderly. J. Leukoc. Biol. 65: 416-427; 1999.

Microglial and Astrocyte Chemokines Regulate Monocyte Migration through the Blood-Brain Barrier in Human Immunodeficiency Virus-1 Encephalitis

“…In other neurodegenerative disorders such as Alzheimer's disease, 35,36 MS, 37 stroke, 38 and Parkinson's disease, the importance of microglial activation in the pathogenesis appears more obvious. 39 Microglia activation (demonstrated by HLA-DR immunoreactivity) 40 -42 and the concomitant secretion of cytokines and chemokines could be crucial events in HIV-1 neuropathogenesis. Microglial nodules are detected perivascularly, and in HIVE are associated with perivascular cuffs of macrophages, suggesting local production of chemokines.…”

Induction of the Formyl Peptide Receptor 2 in Microglia by IFN-γ and Synergy with CD40 Ligand

“…A hallmark of AD is the presence of senile plaques characterized by the deposition of aberrantly produced amyloid peptides (A␤), in particular the 42-aa form A␤ 42 , in association with neuronal damage (1)(2)(3)(4). In addition to its direct neurotoxicity (5), A␤ 42 is a potent activator of microglia, the mononuclear phagocytes in the brain that surround and infiltrate senile plaques composed of A␤ deposits and neurofibrillary tangles in AD (6,7).…”

Nanomedicine in the diagnosis and therapy of neurodegenerative disorders

“…MP can secrete neurotoxins and induce neuronal injury leading to neurocognitive and motor impairments. Clear connections exist between inflammation and neurodegeneration [46,47]. Microglial cells rapidly respond to insults with hypertrophy, proliferation, and expression of proinflammatory cytokines [48].…”