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Neuropathology and Pathogenesis of Encephalitis following Amyloid β Immunization in Alzheimer's Disease

Published on Jan 1, 2004in Brain Pathology 6.19
· DOI :10.1111/j.1750-3639.2004.tb00493.x
Isidre Ferrer72
Estimated H-index: 72
(University of Barcelona),
Mercé Boada Rovira1
Estimated H-index: 1
+ 2 AuthorsFrederic Costa-Jussá1
Estimated H-index: 1
Immunizing transgenic PDAPP mice, which overexpress mutant APP and develop β-amyloid deposition resembling plaques in Alzheimer's disease (AD), results in a decrease of amyloid burden when compared with non treated transgenic animals im-munization with amyloid β peptide has been initiated in a randomised pilot study in AD. Yet a minority of patients developed a neurological complication consistent with meningoencephalitis and one patient died; the trial has been stopped. Neuropathological examination in that patient showed meningoencephalitis and focal atypically low numbers of diffuse and neuritic plaques but not of vascular amyloid nor regression of tau pathology in neurofibrillary tangles and neuropil threads. The present neuropathological study reports the second case of menigoencephalitis following immunization with amyloid-β peptide in AD, and has been directed toward exploring mechanisms underlying decreased tau pathology in relation- with amyliod deposit regression, and possible molecular bases involved in the inflammatory response following immunization. Inflammatory infiltrates were composed of CD8+, CD3+, CD5+ and, rarely, CD7+ lymphocytes, whereas B lymphocytes and T cytotoxic cells CD16, CD57, TIA and graenzyme were negative. Characteristic neuropathological findings were focal depletion of diffuse and neuritic plaques, but not of amyloid angiopathy, and the presence of small numbers of extremely dense(collapsed) plaques surrounded by active microglia, and multinucleated giant cells filled with dense Aβ42and Aβ40, in addition to severe small cerebral blood Reduced amyloid burden was accompanied by low amyloid-associated oxidative stress responses (reduced superoxide dismutase-1:SOD-1 expression) and by local inhibition of the stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) and p38 kinase which are involved in tau phosphorylation. These results support the amyloid cascade of tau phosphorylation in AD regarding phosphorylation of tau in neurofibrillary tangles and β-amyloid deposition in neuritic plaques, but not of tau in neurofibrillary tangles and threads. Furthermore, amyloid reduction was accompanied by increased expression of the PA28α/β inductor, and of LMP7, LMP2 and MECL1 subunits of the immunopro-teasome in microglial and inflammatory cells surrounding collapsed plaques, and in multinucleated giant cells.Immunoproteasome subunit expression was accompanied by local presentation of MHC class molecules. Release of antigenic peptides derived from β-amyloid processing may enhance T-cell inflammatory responses accounting for the meningoencephalitis following amyloid-β peptide immunization
  • References (47)
  • Citations (499)
Published on Jan 1, 2001in Acta Neuropathologica 15.88
Isidre Ferrer72
Estimated H-index: 72
R. Blanco15
Estimated H-index: 15
(University of Barcelona)
+ 4 AuthorsTeresa Ribalta28
Estimated H-index: 28
(University of Barcelona)
Prion protein (PrPC) is a glycolipid-anchored cell membrane sialoglycoprotein that localises in presynaptic membranes. Since synapses are vulnerable to Alzheimer's disease (AD), the present study examines PrPC expression in senile plaques, one of the major structural abnormalities in AD, by single- and double-labelling immunohistochemistry. Punctate PrPC immunoreactivity is found in diffuse plaques, whereas isolated large coarse PrPC-positive granules reminiscent of dystrophic neurites are obser...
76 Citations Source Cite
Published on Jan 1, 1999
Heiko Braak75
Estimated H-index: 75
(Goethe University Frankfurt),
Eva Braak58
Estimated H-index: 58
(Goethe University Frankfurt)
Neuropathologic hallmarks of Alzheimer’s disease (AD) include the progressive deposition of virtually insoluble proteinaceous material in both extracellular and intraneuronal locations. The extracellular deposits consist mainly of Aβ-amyloid-protein (Joachim and Selkoe, 1989; Beyreuther and Masters, 1991; Selkoe, 1991, 1993, 1994); abnormally phosphorylated tau protein (PHF-tau, paired helical filament tau) dominates among the intraneuronal changes (Goedert et al., 1991, 1992; Iqbal and Grundke-...
71 Citations Source Cite
Published on Apr 1, 1998in Journal of Alzheimer's Disease 3.17
George Perry121
Estimated H-index: 121
Rudy J. Castellani48
Estimated H-index: 48
(Case Western Reserve University)
+ 1 AuthorsMark A. Smith119
Estimated H-index: 119
(Case Western Reserve University)
The two most striking features of Alzheimer disease are (i) the multitude of abnormalities affecting essentially every system and (ii) the strict age dependence. Recent work suggests that both features are linked to increased oxidative stress that damages lipids, proteins and nucleic acids and results in redox-active metal accumulations, mitochondrial damage and formation of advanced glycation endproducts. Interestingly, β-protein precursor, amyloid-β, presenilins, and apolipoprotein E have all ...
157 Citations Source Cite
Published on Nov 1, 2002in Journal of Alzheimer's Disease 3.17
Alex E. Roher57
Estimated H-index: 57
Tyler A. Kokjohn29
Estimated H-index: 29
Alzheimer’s Disease (AD) is a progressive neurodegenerative disorder characterized by a time-dependent amyloid fibril deposition in cortical senile plaques and cerebral vascular walls. Several transgenic (Tg) mice have been engineered to overexpress amyloid-beta precursor protein (AβPP) with familial AD mutations. With advancing age, the Tg mice accumulate amyloidbeta (Aβ) peptides, primarily of 40 to 42 amino acids, in plaques and blood vessel wall deposits which resemble morphologically those ...
10 Citations Source Cite
Published on Jan 1, 2003in Acta Neuropathologica 15.88
K. Jelli60
Estimated H-index: 60
Johannes Attems44
Estimated H-index: 44
Recent epidemiological and clinico-pathological data suggest overlaps between Alzheimer's disease (AD) and cerebrovascular lesions (CVL) that may show some synergistic effects, but the results of studies of the relationship between AD and stroke have been controversial. The objective of this study was to compare the frequency of cerebral infarcts, hemorrhages and minor cerebrovascular lesions in autopsy-confirmed AD and age-matched control brains. Using current routine and immunohistochemical me...
83 Citations Source Cite
Published on Jan 1, 1997in Advances in Immunology 5.93
Keui Tanaka1
Estimated H-index: 1
(University of Tokushima),
Nobuyuki Tanahashi20
Estimated H-index: 20
(University of Tokushima)
+ 2 AuthorsNaoki Shimbara25
Estimated H-index: 25
(Sumitomo Electric Industries)
Publisher Summary This chapter discusses the recent findings related to the roles of proteasomes in the major histocompatibility complex (MHC) class I-restricted antigen-processing pathway. One of the most important responses in this antigen-specific immune system is to distinguish correctly non-self-antigens from self-antigens for selective elimination because deviation from this recognition would lead to a variety of opportunistic infections or autoimmune diseases. The chapter focuses on the r...
97 Citations Source Cite
Published on Dec 1, 2002in Acta Neuropathologica 15.88
Isidre Ferrer72
Estimated H-index: 72
Marta Barrachina27
Estimated H-index: 27
(University of Barcelona),
B. Puig26
Estimated H-index: 26
(University of Barcelona)
Tau phosphorylation was examined in Alzheimer's disease (AD), Pick's disease (PiD), progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) using phospho-specific tau antibodies recognizing the phosphorylated form of Ser202, Ser214 and Ser 396, and antibodies to non-phosphorylated glycogen synthase kinase-3α/β (GSK-3α/β), which regulates phosphorylation at these specific sites on tau and phosphorylated GSK-3βSer9 (GSK-3β-P); this antibody is directed to the inactive form of GSK-...
127 Citations Source Cite
Published on Feb 28, 2003in Journal of Neurochemistry 4.61
Susi Keck2
Estimated H-index: 2
Robert Nitsch57
Estimated H-index: 57
+ 1 AuthorsOliver Ullrich33
Estimated H-index: 33
Alzheimer's disease (AD) is characterized neuropathologically by intracellular neurofibrillary tangles (NFTs) formed of tau-based paired helical filaments (PHFs) and extracellular β-amyloid plaques. The degree of Alzheimer dementia correlates with the severity of PHFs and NFTs. As an intraneuronal accumulation of oxidatively damaged proteins has been found in the brains of patients with AD, a dysfunction of the proteasomal system, which degrades damaged proteins, has been assumed to cause protei...
312 Citations Source Cite
Published on Mar 1, 1992in American Journal of Pathology 4.07
Miguel Pappolla4
Estimated H-index: 4
(New York Medical College),
Rawhi Omar9
Estimated H-index: 9
(West Virginia University)
+ 1 AuthorsN. K. Robakis12
Estimated H-index: 12
(Icahn School of Medicine at Mount Sinai)
Membrane and cytoskeletal structures are known targets of oxidative injury. Brains from patients with Alzheimer's disease have cytoskeletal abnormalities and platelet and possible neuronal membrane lesions. The authors have recently demonstrated that superoxide anion is a powerful inducer of heat-shock protein synthesis, and have also shown that in response to oxidative stress or hyperthermia, intracellular levels of antioxidant enzymes increase to several folds. Whether the aforementioned mecha...
304 Citations
Published on May 1, 2002in The Journal of Neuroscience 5.97
Mary J. Savage26
Estimated H-index: 26
Yin-Guo Lin9
Estimated H-index: 9
+ 2 AuthorsRichard W. Scott39
Estimated H-index: 39
The mechanisms by which neurons and synapses are lost in Alzheimer's disease (AD) are not completely understood. To characterize potential signaling events linked to AD pathogenesis, activation-specific antibodies were used to examine mitogen-activated protein kinase (MAPK) kinase pathways at various ages in mice transgenic for human amyloid precursor protein-695 with the Swedish familial AD mutations (Tg2576) and homozygous for a P264L familial AD mutation introduced by targeting of the preseni...
210 Citations Source Cite
Cited By499
Published on Jan 1, 2006in Expert Review of Neurotherapeutics 3.70
Paula I. Moreira58
Estimated H-index: 58
Xiongwei Zhu82
Estimated H-index: 82
+ 2 AuthorsGeorge Perry121
Estimated H-index: 121
4 Citations
Published on Jan 1, 2010
Soluble intermediates of the amyloid-β (Aβ) aggregation process are suggested to play a central role in the pathogenesis of Alzheimer’s disease (AD) by causing synaptic dysf ...
Published on Jan 1, 2010in Advances in Experimental Medicine and Biology 1.76
Klaudia U. Hunter6
Estimated H-index: 6
(University of Michigan),
Chester K. Yarbrough13
Estimated H-index: 13
(Washington University in St. Louis),
Joseph D. Ciacci10
Estimated H-index: 10
(University of California, San Diego)
Neurodegenerative diseases comprise an important group of chronic diseases that increase in incidence with rising age. In particular, the two most common neurodegenerative diseases are Alzheimer’s disease and Parkinson’s disease, both of which will be discussed below. A third, Huntington’s disease, occurs infrequently, but has been studied intensely. Each of these diseases shares characteristics which are also generalizeable to other neurodegenerative diseases: accumulation of proteinaceous subs...
10 Citations Source Cite
Published on Jan 1, 2009
Justine T. Tigno-Aranjuez8
Estimated H-index: 8
(Case Western Reserve University)
Published on Jan 1, 2009
William E. Klunk81
Estimated H-index: 81
(University of Pittsburgh),
Chester A. Mathis74
Estimated H-index: 74
(University of Pittsburgh)
+ 5 AuthorsRobert D. Nebes48
Estimated H-index: 48
(University of Pittsburgh)
3 Citations Source Cite
Published on Jan 1, 2007
Liana G. Apostolova35
Estimated H-index: 35
(University of California, Los Angeles),
Jeffrey L. Cummings132
Estimated H-index: 132
(University of California, Los Angeles)
Alzheimer’s disease (AD) is the most common neurodegenerative disease and the leading cause for cognitive decline in the elderly. The disease results in relentlessly progressive decline in intellectual function and gradual loss of activities of daily living. Ninety percent of AD patients have late onset “sporadic” AD. Only 10% become symptomatic before age 65. Two percent of AD is familial and is caused by autosomal dominant genetic mutations. AD is caused by the aberrant folding and aggregation...
4 Citations Source Cite
Published on Jan 1, 2004
Cerebral amyloid angiopathy (CAA) is characterized by the deposition of congophilic material within the walls of small to medium-sized blood vessels of the brain and leptomeninges. The incidence of CAA increases with aging, and in its most severe stages, the vascular amyloid causes a breakdown of the blood vessel wall which results in spontaneous, often recurrent, lobar intracerebral hemorrhage. CAA is estimated to account for four to twenty percent of all nontraumatic intracerebral hemorrhages....
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Published on Jan 1, 2008
John R. Cirrito44
Estimated H-index: 44
(Washington University in St. Louis),
David M. Holtzman118
Estimated H-index: 118
(Washington University in St. Louis)
ABSTRACT Accumulation of the amyloid-β (Aβ) peptide in different aggregated conformations within the brain is central to the pathogenesis of Alzheimer's disease (AD). In brains of AD patients, amyloid plaques are surrounded by swollen, dystrophic neurites. Particular aggregated species of Aβ are also toxic to neurons and are proposed to inhibit synaptic transmission. In order to prevent or reverse Aβ-related pathology, several therapeutic strategies are aimed at reducing brain Aβ levels. For ins...
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Published on Jan 1, 2006
Isidro Ferrer57
Estimated H-index: 57
(University of Barcelona),
Gabriel Santpere18
Estimated H-index: 18
(University of Barcelona),
B. Puig26
Estimated H-index: 26
(University of Barcelona)
1 Citations Source Cite
Published on Jan 1, 2007
William L. Klein65
Estimated H-index: 65
(Northwestern University),
Pascale N. Lacor22
Estimated H-index: 22
(Northwestern University)
+ 1 AuthorsSergio T. Ferreira1
Estimated H-index: 1
(Northwestern University)
Individuals with early Alzheimer’s disease (AD) suffer from a selective and profound failure to form new memories. A novel molecular mechanism with implications for therapeutics and diagnostics is now emerging in which the specificity of AD for memory derives from disruption of plasticity at synapses targeted by neurologically active Aβ oligomers. We have named these oligomers “ADDLs” (for pathogenic Aβ-derived diffusible ligands). ADDLs constitute metastable alternatives to the disease-defining...
19 Citations Source Cite