Abstract：
:α-Synuclein (αSyn) histopathology defines several neurodegenerative disorders, including Parkinson's disease, Lewy body dementia, and Alzheimer's disease (AD). However, the functional link between soluble αSyn and disease etiology remains elusive, especially in AD. We, therefore, genetically targeted αSyn in APP transgenic mice modeling AD and mouse primary neurons. Our results demonstrate bidirectional modulation of behavioral deficits and pathophysiology by αSyn. Overexpression of human wild-type αSyn in APP animals markedly reduced amyloid deposition but, counter-intuitively, exacerbated deficits in spatial memory. It also increased extracellular amyloid-β oligomers (AβOs), αSyn oligomers, exacerbated tau conformational and phosphorylation variants associated with AD, and enhanced neuronal cell cycle re-entry (CCR), a frequent prelude to neuron death in AD. Conversely, ablation of the SNCA gene encoding for αSyn in APP mice improved memory retention in spite of increased plaque burden. Reminiscent of the effect of MAPT ablation in APP mice, SNCA deletion prevented premature mortality. Moreover, the absence of αSyn decreased extracellular AβOs, ameliorated CCR, and rescued postsynaptic marker deficits. In summary, this complementary, bidirectional genetic approach implicates αSyn as an essential mediator of key phenotypes in AD and offers new functional insight into αSyn pathophysiology.
journal_name
Acta Neuropatholjournal_title
Acta neuropathologicaauthors
Khan SS,LaCroix M,Boyle G,Sherman MA,Brown JL,Amar F,Aldaco J,Lee MK,Bloom GS,Lesné SEdoi
10.1007/s00401-018-1886-zsubject
Has Abstractpub_date
2018-10-01 00:00:00pages
589-605issue
4eissn
0001-6322issn
1432-0533pii
10.1007/s00401-018-1886-zjournal_volume
136pub_type
杂志文章abstract：:The alterations in oligodendrocytes in myelin basic protein-induced acute experimental autoimmune encephalomyelitis (EAE) in the Lewis rat were studied using the technique of pre-embedding immunolabelling with the Rip monoclonal antibody, which specifically labels the cytoplasm of the cell bodies and processes of olig...
journal_title：Acta neuropathologica
pub_type： 杂志文章
doi：10.1007/s004010050763
更新日期：1998-01-01 00:00:00
abstract：:Neurological signs were observed in 3 lambs at approximately 1 month of age, in a flock of 1 ram and 29 ewes with 43 lambs. Deterioration occurred such that the lambs had either died or been killed by 4 months of age. Necropsies of two of these lambs revealed a diffuse encephalopathy in which the most prominent featur...
journal_title：Acta neuropathologica
pub_type： 杂志文章
doi：10.1007/BF00309632
更新日期：1995-01-01 00:00:00
abstract：:A murine model of Tay-Sachs disease, the prototype of the GM2 gangliosidoses, was produced through the targeted disruption of the Hexa gene encoding the subunit of alpha-hexosaminidase A. The mice were completely devoid of beta-hexosaminidase A activity and accumulated GM2 ganglioside in the CNS in an age-dependent ma...
journal_title：Acta neuropathologica
pub_type： 杂志文章
doi：10.1007/BF00309622
更新日期：1995-01-01 00:00:00
abstract：:A complex neuropathological study of two cases of Niemann-Pick disease (NPD) type C (NPDC) revealed some novel features in the chemical pathology of the neuronal storage. Lipid histochemistry showed the presence of a lipid which met the criteria of a neuronal glycosphingolipid. Sphingomyelin (SM) was not detected in t...
journal_title：Acta neuropathologica
pub_type： 杂志文章
doi：10.1007/BF00690966
更新日期：1985-01-01 00:00:00
abstract：:In this report, we describe the clinical, topographical and immunohistochemical characteristics of neurofilament (NF) inclusion formation induced by the intracisternal inoculation of young adult New Zealand white rabbits at 28-day intervals with 100 micrograms AlCl3 over the course of 267 days. The ability to recover ...
journal_title：Acta neuropathologica
pub_type： 杂志文章
doi：10.1007/BF00294460
更新日期：1995-01-01 00:00:00
abstract：:The effect of the cytokine, colony stimulating factor-1 (CSF-1), on neuronal survival in cerebral cortex ischemic lesion was determined. Ischemic lesions were made in C3H/HeJ mice by disrupting blood vessels that penetrate the cerebral cortex from the pial-vascular plexus. Recombinant human colony stimulating factor 1...
journal_title：Acta neuropathologica
pub_type： 杂志文章
doi：10.1007/s004010050550
更新日期：1996-11-01 00:00:00
abstract：:Neurotropic herpesviruses can establish lifelong infection in humans and contribute to severe diseases including encephalitis and neurodegeneration. However, the mechanisms through which the brain's immune system recognizes and controls viral infections propagating across synaptically linked neuronal circuits have rem...
journal_title：Acta neuropathologica
pub_type： 杂志文章
doi：10.1007/s00401-018-1885-0
更新日期：2018-09-01 00:00:00
abstract：:Histomorphological and histochemical variability was studied in muscle specimens from 30 patients with congenital muscular dystrophy (CMD). We found involvement of the central nervous system in 8 patients (Fukuyama CMD, F-CMD), involvement of the brain and the eyes in 5 patients (muscle, eye and brain disease, MEB-D) ...
journal_title：Acta neuropathologica
pub_type： 杂志文章
doi：10.1007/BF00369452
更新日期：1993-01-01 00:00:00
abstract：:HTLV-III-like particles were observed within a cell process surrounded by a myelin sheath, in the brain of a 4-year-old boy with AIDS encephalopathy. Similar particles were also observed in the mononuclear macrophage-like cells. ...
journal_title：Acta neuropathologica
pub_type： 杂志文章
doi：10.1007/BF00686627
更新日期：1987-01-01 00:00:00
abstract：:A description is given of three cases of ganglioneuromas, which originated from ganglia of the sympathetic chain of hamsters. Other reports of such tumors in this species are reviewed and the literature relative to hamster ganglioneuromas presented. In addition, the possible genesis of origin from adult ganglion cells...
journal_title：Acta neuropathologica
pub_type： 杂志文章
doi：10.1007/BF00696794
更新日期：1975-10-01 00:00:00
abstract：:Skeins or skein-like inclusions, one of the two types of ubiquitinated intraneuronal inclusions in amyotrophic lateral sclerosis (ALS), in the neostriatum are not specific to the disease, but it has not yet been determined whether the other, spherical or crescent-shaped inclusions (SCI) are pathognomonic. To clarify t...
journal_title：Acta neuropathologica
pub_type： 杂志文章
doi：10.1007/s004010100398
更新日期：2001-11-01 00:00:00
abstract：:Little information is available regarding the morphological changes in the mitochondria in amyotrophic lateral sclerosis (ALS). In particular, mitochondrial changes in dorsal root ganglion cells have not yet been examined. We therefore conducted an electron microscopic examination of the mitochondria in dorsal root ga...
journal_title：Acta neuropathologica
pub_type： 杂志文章
doi：10.1007/s00401-007-0299-1
更新日期：2007-12-01 00:00:00
abstract：:Peroxidase-labeled lectins were used for detection of specific monosaccharide residues in amyloid plaques in brains of scrapie-infected mice. The lectins tested recognize the following residues: beta-D-galactosyl (Ricinus communis agglutinin 120, RCA-1), alpha-D-galactosyl and alpha-D-galactopyranoside (Bandeirea simp...
journal_title：Acta neuropathologica
pub_type： 杂志文章
doi：10.1007/BF00688295
更新日期：1986-01-01 00:00:00
abstract：:The cytoskeletal properties and endogenous degradation of intermediate filaments in cultured human glioma cells (U-251MG) were studied using monoclonal antibodies in immunohistochemical and immunochemical methods. Both glial fibrillary acidic protein (GFAP)- and vimentin-antibodies gave a fibrillar cytoplasmic stainin...
journal_title：Acta neuropathologica
pub_type： 杂志文章
doi：10.1007/BF00687041
更新日期：1986-01-01 00:00:00
abstract：:The mechanisms underlying neurodegenerative diseases are the outcome of pathological alterations of evolutionary conserved molecular and cellular cascades. For this reason, Drosophila and C. elegans serve as useful model systems to study various aspects of neurodegenerative diseases. Here, we introduce the advantageou...
journal_title：Acta neuropathologica
pub_type： 杂志文章
doi：10.1007/s00401-010-0689-7
更新日期：2010-08-01 00:00:00
abstract：:The extent of DNA fragmentation analysed using the TUNEL technique was evaluated in post-mortem human brain tissue. Twenty-four patients with clinical and histopathological diagnosis of Alzheimer's disease (AD) and a short post-mortem delay were analysed. We report an increase in the count of TUNEL-labelled cells as t...
journal_title：Acta neuropathologica
pub_type： 杂志文章
doi：10.1007/s004010000228
更新日期：2000-12-01 00:00:00
abstract：:Multiple different pathological protein aggregates are frequently seen in human postmortem brains and hence mixed pathology is common. Mixed dementia on the other hand is less frequent and neuropathologically should only be diagnosed if criteria for more than one full blown disease are met. We quantitatively measured ...
journal_title：Acta neuropathologica
pub_type： 杂志文章
doi：10.1007/s00401-015-1406-3
更新日期：2015-05-01 00:00:00
abstract：:Using a four-step immunoperoxidase (PAP) method and the monoclonal antibody MAbA9-C6 (MAbA9-C6), which defines an epitope of the retinal S-antigen (S-Ag), we investigated the S-Ag immunoreactivity in human fetal, newborn, infantile and adult pineal glands and in 13 human pineal parenchymal tumors. S-Ag immunoreactivit...
journal_title：Acta neuropathologica
pub_type： 杂志文章
doi：10.1007/BF00688043
更新日期：1986-01-01 00:00:00
abstract：:Essential mixed cryoglobulinemia, which can cause hypersensitivity vasculitis, was observed in five patients with peripheral neuropathy. Three cases presented with multifocal neuropathies and two cases with symmetrical polyneuropathy. One had cryoglobulinemia with IgM monoclonal gammopathy IgG polyclonal gammopathy, a...
journal_title：Acta neuropathologica
pub_type： 杂志文章
doi：10.1007/BF00686206
更新日期：1988-01-01 00:00:00
abstract：:A large series of central and peripheral nervous system tumors was studied for the presence of glial fibrillary acidic protein (GFAP) and gamma-enolase (neuron-specific enolase, NSE), using specific monoclonal antibodies (mAbs). Occurrence in and specificity of GFAP to glial and mixed tumors was confirmed and depended...
journal_title：Acta neuropathologica
pub_type： 杂志文章
doi：10.1007/BF00687791
更新日期：1988-01-01 00:00:00
abstract：:Excitotoxicity is considered a major cell death inductor in neurodegeneration. Yet the mechanisms involved in cell death and cell survival following excitotoxic insults are poorly understood. Expression of active, phosphorylation-dependent mitogen-activated extracellular signal-regulated kinases (MAPK/ERKs), stress-ac...
journal_title：Acta neuropathologica
pub_type： 杂志文章
doi：10.1007/s00401-001-0481-9
更新日期：2002-04-01 00:00:00
abstract：:Nodding syndrome is an epidemic neurologic disorder of unknown cause that affects children in the subsistence-farming communities of East Africa. We report the neuropathologic findings in five fatal cases (13-18 years of age at death) of nodding syndrome from the Acholi people in northern Uganda. Neuropathologic exami...
journal_title：Acta neuropathologica
pub_type： 杂志文章
doi：10.1007/s00401-018-1909-9
更新日期：2018-11-01 00:00:00
abstract：:Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and a phenotypically similar recessive condition (CARASIL) have emerged as important genetic model diseases for studying the molecular pathomechanisms of cerebral small vessel disease (SVD). CADASIL, the most frequent ...
journal_title：Acta neuropathologica
pub_type： 杂志文章
doi：10.1007/s00401-018-1853-8
更新日期：2018-07-01 00:00:00
abstract：:Brain metastases (BM) are common in cancer patients and are associated with high morbidity and poor prognosis, even after intensive multimodal therapy including resection, radiotherapy (stereotactic radiosurgery or whole brain radiotherapy) and chemotherapy. However, advances in the understanding of the pathobiology o...
journal_title：Acta neuropathologica
pub_type： 杂志文章,评审
doi：10.1007/s00401-011-0933-9
更新日期：2012-02-01 00:00:00
abstract：:Tumours of the neuroglia, 172 in all (50 glioblastomas, 65 fibrillar and gemistocytic astrocytomas, 26 pilocytic astrocytomas and 31 oligodendrogliomas), were studied by automated microscopic picture analysis. Thirteen morphometric and densitometric parameters of the tumour cell nuclei as well as two mitotic parameter...
journal_title：Acta neuropathologica
pub_type： 杂志文章
doi：10.1007/BF00692692
更新日期：1982-01-01 00:00:00
abstract：:Amyloid-beta (Abeta) deposition in cerebral blood vessel walls is one of the key features of Alzheimer's disease (AD). Abeta(1-40) carrying the "Dutch" mutation (DAbeta(1-40)) induces rapid degeneration of cultured human brain pericytes (HBP). To study the mechanisms of this Abeta-induced toxicity, a comparative cDNA ...
journal_title：Acta neuropathologica
pub_type： 杂志文章
doi：10.1007/s00401-002-0585-x
更新日期：2002-11-01 00:00:00
abstract：:The dynamics of cerebrospinal fluid (CSF) tau and Aβ biomarkers over time in Alzheimer's disease (AD) patients from prodromal pre-symptomatic to severe stages of dementia have not been clearly defined and recent studies, most of which are cross-sectional, present conflicting findings. To clarify this issue, we analyze...
journal_title：Acta neuropathologica
pub_type： 杂志文章
doi：10.1007/s00401-013-1151-4
更新日期：2013-11-01 00:00:00
abstract：:Electronmicroscope studies have been performed on the greater splanchnic nerve and the nerve to the medial head of gastrocnemius muscle of control and acrylamide poisoned cats. Degeneration of unmyelinated as well as of myelinated fibres was observed in both nerves. In cats severely poisoned with acrylamide, some very...
journal_title：Acta neuropathologica
pub_type： 杂志文章
doi：10.1007/BF01273262
更新日期：1978-04-26 00:00:00
abstract：:Spinal and bulbar muscular atrophy (SBMA) is a neuromuscular disease caused by the expansion of a polyglutamine tract in the androgen receptor (AR). The mechanism by which expansion of polyglutamine in AR causes muscle atrophy is unknown. Here, we investigated pathological pathways underlying muscle atrophy in SBMA kn...
journal_title：Acta neuropathologica
pub_type： 杂志文章
doi：10.1007/s00401-016-1550-4
更新日期：2016-07-01 00:00:00
abstract：:We described a new type of cytoplasmic inclusion in the choroidal epithelial cells of humans. The inclusions usually appeared as brown, round or elongated bodies with or without an inner core, ranging in size from 1.3 to 7.0 micron. Histochemically, they contained polysaccharides, proteins and compound lipids. Ultrast...
journal_title：Acta neuropathologica
pub_type： 杂志文章
doi：10.1007/BF00687675
更新日期：1988-01-01 00:00:00
