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Cholesterol and IBM.


= For example, recent articles usually refer to abnormal accumulations of cholesterol:
Microsc Res Tech. 2005 Aug 15;67(3-4):114-120 [Epub ahead of print]
Molecular pathology and pathogenesis of inclusion-body myositis.
Askanas V, Engel WK.
USC Neuromuscular Center, Department of Neurology, University of Southern California Keck School of Medicine, Good Samaritan Hospital, Los Angeles, California 90017-1912.
ABSTRACT
We summarize the molecular phenotype, diagnostic criteria, and the newest advances related to seeking the pathogenic mechanism(s) of sporadic inclusion-body myositis (s-IBM), a muscle disease usually of persons over age 50. On the basis of our research, several processes seem to be important in relation to the still-speculative pathogenesis: 1) increased transcription and accumulation of amyloid-b precursor protein (AbPP), and accumulation of its proteolytic fragment Ab; 2) abnormal accumulation of cholesterol, caveolin-1, and apolipoprotein E; 3) oxidative stress; 4) accumulations of intramuscle fiber multiprotein aggregates; and 5) evidence that unfolded/misfolded proteins participate in s-IBM pathogenesis. Our basic hypothesis is that overexpression of AbPP within the aging muscle fibers is an early upstream event causing a subsequent pathogenic cascade.
CONCLUSION
We have presented what we consider the most relevant findings related to the pathogenesis of s-IBM. These have not yet provided a definitive cause and treatment, but they have pointed to potentially exciting avenues for exploring treatment approaches to benefiting s-IBM patients. Examples are identification of factors that would: 1) decrease intramuscle fiber expressions of b- and g-secretases which might lead to decreased production of intracellularly toxic oligomeric Ab42; 2) detoxify free radicals or prevent their formation within muscle fibers; 3) prevent misfolding/unfolding of muscle-fiber proteins and/or enhance their disposal; and 4) decrease protein aggregation.
Microsc. Res. Tech. 67:114-120, 2005. (c) 2005 Wiley-Liss, Inc. August, 2005

= J Neurol Sci. 2005 Mar 15;229-230(1):233-40. Epub 2004 Dec 16.
Cholesterol homeostasis failure as a unifying cause of synaptic degeneration.
Koudinov AR, Koudinova NV. Neurobiology of Lipids, P.O. Box 1665, Rehovot 76100, Israel; Russian Academy of Medical Sciences, Timoshenko St., 38-27, Moscow 121359, Russia.
We previously showed that fine tuning of neural cholesterol dynamics is essential for basic synapse function, plasticity and behavior. Significant experimental evidence indicates that cholinergic function, ionotropic and metabotropic receptor machinery, excessive tau phosphorylation, the change of amyloid beta (Abeta or Abeta) biochemistry, neural oxidative stress reactions, and other features of neurodegeneration also depend on fine tuning of brain cholesterol homeostasis. This evidence suggest that (i) cholesterol homeostasis break is the unifying primary cause of sporadic and familial Alzheimer's disease (AD), neuromuscular diseases (particularly inclusion-body myositis), Niemann-Pick's type C disease and Down syndrome, and (ii) explains the overlap of neurodegenerative hallmarks across the spectrum of neurodegenerative diseases. Provided is evidence-based explanation of why extremely rare (but scientifically popular) cases of AD associated with mutations in amyloid beta protein precursor (APP) and presenilin (PS) genes, are translated into the disorder via membrane cholesterol sensitivity of APP processing by secretases and Abeta generation. The reciprocal effect of Abeta on cholesterol synthesis, cellular uptake, efflux and esterification is summarized, as well as the potential implication of such biological function for the compensatory Abeta-assisted restoration of the synaptic long-term potentiation (LTP) and resulting inability of tackling amyloid to cure AD. PMID: 15760645 [PubMed - in process]

= J Child Neurol. 2003 Mar;18(3):185-90.
Unfolding story of inclusion-body myositis and myopathies: role of misfolded proteins, amyloid-beta, cholesterol, and aging.
Askanas V, Engel WK. USC Neuromuscular Center, Department of Neurology, University of Southern California Keck School of Medicine, Good Samaritan Hospital, Los Angeles, CA 90017-1912, USA. askanas@hsc.usc.edu
Sporadic inclusion-body myositis and hereditary inclusion-body myopathies are progressive muscle diseases leading to severe disability. We briefly summarize their clinical pictures and pathologic diagnostic criteria and discuss the latest advances in illuminating their pathogenic mechanism(s). We emphasize how different etiologies might lead to the strikingly similar pathology and possibly similar pathogenic cascade. On the basis of our research, several processes seem to be important in relation to the still speculative pathogenesis, including (a) increased transcription and accumulation of amyloid-beta precursor protein and accumulation of its proteolytic fragment amyloid-beta; (b) abnormal accumulation of components related to lipid metabolism, for example, cholesterol, accumulation of which is possibly owing to its abnormal trafficking; (c) oxidative stress; (d) accumulations of other Alzheimer's disease-related proteins; and (e) a milieu of muscle cellular aging in which these changes occur. We discuss a potentially very important role of unfolded and/or misfolded proteins as a possible mechanism in the formations of the inclusion bodies and other abnormalities. Publication Types: Lectures PMID: 12731644 [PubMed - indexed for MEDLINE]

= Curr Opin Neurol. 2002 Oct;15(5):525-31.
Inclusion-body myositis and myopathies: different etiologies, possibly similar pathogenic mechanisms.
Askanas V, Engel WK. USC Neuromuscular Center, Department of Neurology, University of Southern California Keck School of Medicine, Good Samaritan Hospital, Los Angeles, California 90017, USA. askanas@hsc.usc.edu
PURPOSE OF REVIEW: Sporadic inclusion-body myositis (s-IBM) and hereditary inclusion body myopathies are progressive muscle diseases that lead to severe disability. We discuss recent advances in illuminating their pathogenic mechanism(s). RECENT FINDINGS: We emphasize how different etiologies might lead to the strikingly similar pathology and possibly similar pathogenic cascade. Our basic hypothesis is that over-expression of amyloid-beta precursor protein within aging muscle fibers is an early upstream event causing the subsequent pathogenic cascade. On the basis of our research, several processes seem to be important in relation to the still speculative pathogenesis: (a) increased transcription and accumulation of amyloid-beta precursor protein, and accumulation of its proteolytic fragment Abeta; (b) accumulations of phosphorylated tau and other Alzheimer-related proteins; (c) accumulation of cholesterol and low-density lipoprotein receptors, the cholesterol accumulation possibly due to its abnormal trafficking; (d) oxidative stress; and (e) a milieu of muscle cellular aging in which these changes occur. We discuss unfolded and/or misfolded proteins as a possible mechanism in formation of the inclusion bodies and their consequences. The remarkable pathologic similarities between s-IBM muscle and Alzheimer disease brain are discussed. SUMMARY: Unfolding knowledge of the various pathogenetic aspects of the s-IBMs and hereditary inclusion body myopathies may lead to new therapeutic avenues. Publication Types: Review Review, Tutorial PMID: 12351995 [PubMed - indexed for MEDLINE]

= Curr Rheumatol Rep. 2002 Oct;4(5):427-33.
Newest pathogenetic considerations in inclusion-body myositis: possible role of amyloid-beta, cholesterol, relation to aging and to Alzheimer's disease.
Askanas V, Engel WK. University of Southern California Neuromuscular Center, Good Samaritan Hospital, 637 South Lucas Avenue, Los Angeles, CA 90017-1912, USA. askanas@hsc.usc.edu
This report summarizes clinical features and diagnostic criteria, and the newest advances related to seeking the pathogenic mechanism(s) of sporadic inclusion-body myositis. On the basis of the authors' research, several processes seem to be important in relation to the still-speculative pathogenesis: increased transcription and accumulation of amyloid-b precursor protein and accumulation of its proteolytic fragment amyloid-b; abnormal accumulation of components related to lipid metabolism (eg, low-density lipoprotein receptors and cholesterol; accumulation of cholesterol is possibly caused by its abnormal trafficking); oxidative stress; accumulations of other Alzheimer-related proteins including phosphorylated tau; a milieu of muscle cellular aging in which these changes occur. The authors' basic hypothesis is that overexpression of amyloid-b precursor protein within the aging muscle fibers is an early upstream event causing the subsequent pathogenic cascade. The remarkable pathologic similarities between inclusion-body myositis muscle and Alzheimer's disease brain are discussed. Publication Types: Review Review, Tutorial PMID: 12217248 [PubMed - indexed for MEDLINE]

= Neurology. 2002 Feb 12;58(3):438-45.
Three lipoprotein receptors and cholesterol in inclusion-body myositis muscle.
Jaworska-Wilczynska M, Wilczynski GM, Engel WK, Strickland DK, Weisgraber KH, Askanas V. USC Neuromuscular Center, Department of Neurology, University of Southern California Keck School of Medicine, Good Samaritan Hospital, 637 S. Lucas Ave., Los Angeles, CA 90017-1912, USA.
BACKGROUND: An important aspect of inclusion-body myositis (IBM) vacuolated muscle fibers (VMF) is abnormal accumulation of amyloid-beta precursor protein (AbetaPP) epitopes and its product, amyloid-beta (Abeta), and of phosphorylated tau (p-tau) in the form of paired helical filaments. Lipoprotein receptors and cholesterol are known to play an important role in AbetaPP processing, Abeta production, and tau phosphorylation. METHODS: In 10 IBM and 22 control muscle biopsies the authors immunolocalized low-density lipoprotein receptor (LDLR), very low-density lipoprotein receptor (VLDLR), and low-density lipoprotein receptor-related protein (LRP), and colocalized them with Abeta, p-tau, APOE, and free cholesterol. RESULTS: In each biopsy, virtually all IBM VMF had strong LDLR-immunoreactive inclusions, which colocalized with Abeta, APOE, p-tau, and free cholesterol. VLDLR was increased mainly diffusely, but in approximately 50% of the VMF it was also accumulated in the form of inclusions colocalizing with Abeta, APOE, and free cholesterol, but not with p-tau. LRP inclusions were present in a few VMF. In all myopathies, a subset of regenerating and necrotizing muscle fibers had prominent diffuse accumulation of both LDLR and free cholesterol. At normal neuromuscular junctions (NMJ) postsynaptically, LDLR and VLDLR, but not LRP, were immunoreactive. CONCLUSIONS: 1) Abnormal accumulation of LDLR, VLDLR, LRP, and cholesterol within IBM vacuolated muscle fibers suggests novel roles for them in the IBM pathogenesis. 2) Expression of LDLR and VLDLR at normal NMJ suggests physiologic roles for them in transsynaptic signaling pathways, increased internalization of lipoproteins there, or both. 3) Increased LDLR and free cholesterol in some regenerating and necrotizing muscle fibers suggest a role for them in human muscle fiber growth and repair and necrotic death. PMID: 11839845 [PubMed - indexed for MEDLINE]

= Curr Opin Neurol Neurosurg. 1992 Oct;5(5):645-54.
Inflammatory and toxic myopathies.
Dalakas MC. Neuromuscular Diseases Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland.
The major advances in the immunopathogenesis and treatment of inflammatory myopathies, and the main criteria that distinguish polymyositis (PM) from dermatomyositis (DM) or inclusion-body myositis (IBM) are presented. The origin and implications of the amyloid and ubiquitin deposits found within the vacuolated fibers of patients with IBM are considered. The pathogenesis of human immunodeficiency virus (HIV) and human T-cell lymphotrophic virus (HTLV)-I-associated PM is presented, and the role of retroviruses in triggering PM, even in the absence of detectable viral genome within the muscle fibers, is discussed. In addition, three toxic myopathies with distinct morphologic, biochemical, or molecular characteristics, caused by zidovudine [azidothymidine (AZT) myopathy], the cholesterol-lowering-agent myopathy (CLAM), and the combination of blocking agents with corticosteroids are presented. Publication Types: Review Review, Tutorial PMID: 1327303 [PubMed - indexed for MEDLINE]


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