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1.
Mol Psychiatry ; 21(12): 1790-1798, 2016 12.
Article in English | MEDLINE | ID: mdl-26830137

ABSTRACT

Abundant tau inclusions are a defining hallmark of several human neurodegenerative diseases, including Alzheimer's disease. Protein fragmentation is a widely observed event in neurodegenerative proteinopathies. The relevance of tau fragmentation for the neurodegenerative process in tauopathies has yet remained unclear. Here we found that co-expression of truncated and full-length human tau in mice provoked the formation of soluble high-molecular-weight tau, the failure of axonal transport, clumping of mitochondria, disruption of the Golgi apparatus and missorting of synaptic proteins. This was associated with extensive nerve cell dysfunction and severe paralysis by the age of 3 weeks. When the expression of truncated tau was halted, most mice recovered behaviorally and functionally. In contrast, co-expression of full-length tau isoforms did not result in paralysis. Truncated tau thus induces extensive but reversible neurotoxicity in the presence of full-length tau through the formation of nonfilamentous high-molecular-weight tau aggregates, in the absence of tau filaments. Targeting tau fragmentation may provide a novel approach for the treatment of human tauopathies.


Subject(s)
Tauopathies/metabolism , tau Proteins/metabolism , Alzheimer Disease/metabolism , Animals , Axonal Transport , Brain/metabolism , Disease Models, Animal , Humans , Mice , Mice, Transgenic , Neurons/metabolism , Neurotoxicity Syndromes/metabolism , Protein Isoforms/metabolism , Protein Structural Elements/physiology , tau Proteins/analysis
2.
J Neurol ; 255(1): 77-88, 2008 Jan.
Article in English | MEDLINE | ID: mdl-18204807

ABSTRACT

Several hereditary conditions affecting cerebral, retinal and systemic microvessels have recently been described. They include CADASIL, CRV, and HERNS. We here report on a variant form of a hereditary systemic angiopathy (HSA) affecting two generations of a Caucasian family. Clinical symptoms of HSA appear in the mid-forties and are characterized by visual impairment, migraine-like headache, skin rash, epileptic seizures, progressive motor paresis and cognitive decline. Late symptoms include hepatic and renal failure. Retinal capillary microaneurysms and arteriolar tortuosity are associated with marked optic disc atrophy. Radiological hallmarks consist of multiple cerebral calcifications and tumor-like subcortical white matter lesions. Brain, peripheral nerve, muscle, kidney and colon biopsies have revealed a multi organ small vessel involvement with partly altered endothelium, perivascular inflammation and thrombotic microangiopathy. No curative therapeutic options are known for hereditary cerebral vasculopathies. The use of cyclophosphamide, azathioprine and methotrexate was of no benefit in our cases of HSA. Early diagnosis of hereditary systemic angiopathies is important in order to prevent patients from repetitive invasive diagnostic measures and to avoid the use of inappropriate and potentially harmful drugs.


Subject(s)
Cerebral Arterial Diseases/pathology , Kidney Diseases/pathology , Liver Diseases/pathology , Retinal Diseases/pathology , Vascular Diseases/pathology , Adult , Aged , Brain/blood supply , Brain/pathology , Brain/physiopathology , Calcinosis/pathology , Calcinosis/physiopathology , Cerebral Arterial Diseases/physiopathology , Cerebral Arteries/pathology , Cerebral Arteries/physiopathology , Disease Progression , Early Diagnosis , Female , Humans , Immunosuppressive Agents/therapeutic use , Kidney Diseases/physiopathology , Liver Diseases/physiopathology , Liver Failure/pathology , Liver Failure/physiopathology , Male , Microcirculation/pathology , Microcirculation/physiopathology , Middle Aged , Renal Insufficiency/pathology , Renal Insufficiency/physiopathology , Retinal Artery/pathology , Retinal Artery/physiopathology , Retinal Diseases/physiopathology , Syndrome , Treatment Outcome , Vascular Diseases/physiopathology , Vasculitis/pathology , Vasculitis/physiopathology , Viscera/blood supply , Viscera/pathology , Viscera/physiopathology
4.
AJNR Am J Neuroradiol ; 27(6): 1272-4, 2006.
Article in English | MEDLINE | ID: mdl-16775278

ABSTRACT

Palatal tremor (PT), also known as palatal myoclonus, is defined by short rhythmic contractions of the palatal musculature. Functional MR imaging (fMRI) revealed prominent bilateral neuronal activation in the putamen associated with essential palatal tremor (EPT) in a 41-year-old man. This implies a central role of the putamen in EPT, most likely as a consequence of diminished inhibition in an afferent pathway. Because fMRI primarily detects activations, dysfunctional areas remain obscure. The present functional study complements previous pathologic studies, which associated PT with lesions to dentate nucleus, red nucleus, and the inferior olive (Guillain-Mollaret triangle).


Subject(s)
Brain Mapping , Essential Tremor/physiopathology , Magnetic Resonance Imaging , Palatal Muscles/physiopathology , Putamen/physiopathology , Adult , Afferent Pathways , Humans , Male , Muscle Contraction , Neck Muscles/physiopathology
7.
Exp Neurol ; 168(2): 364-72, 2001 Apr.
Article in English | MEDLINE | ID: mdl-11259124

ABSTRACT

Mongolian gerbils are epilepsy-prone animals. In adult gerbils two major groups can be differentiated according to their seizure behavior: Highly seizure-sensitive gerbils exhibit facial and forelimb clonus or generalized tonic-clonic seizures from the first test on, while kindled-like gerbils are seizure free for the first three to six consecutive tests, later develop forelimb myoclonus, and eventually progress to generalized tonic-clonic seizures. In the hippocampus, seizure history of the individual animal is mirrored in the intensity in which GABAergic neurons are immunostained for the calcium-binding protein parvalbumin: they lose parvalbumin with increasing seizure incidence. In a first step to clarify the influence of hippocampal projection neurons on spontaneous seizure behavior and related parvalbumin expression, we induced degeneration of the CA1 pyramidal cells by transient forebrain ischemia. This results in a decreased seizure sensitivity in highly seizure-sensitive gerbils. The kindling-like process, however, is not permanently blocked by the ischemic nerve cell loss, suggesting that an intact CA1 field is not a prerequisite for the development of seizure behavior. The seizure-induced loss of parvalbumin from the ischemia-resistant interneurons recovers after ischemia. Thus, changes in parvalbumin content brought about by repeated seizures are not permanent but can rather be modulated by novel stimuli.


Subject(s)
Brain Ischemia/metabolism , Epilepsy/metabolism , Interneurons/metabolism , Nerve Degeneration/metabolism , Parvalbumins/metabolism , Pyramidal Cells/metabolism , Animals , Brain Ischemia/pathology , Epilepsy/prevention & control , Gerbillinae , Hippocampus/metabolism , Hippocampus/pathology , Interneurons/pathology , Male , Nerve Degeneration/pathology , Pyramidal Cells/pathology , Rats
8.
J Neurosci ; 21(5): 1619-27, 2001 Mar 01.
Article in English | MEDLINE | ID: mdl-11222652

ABSTRACT

A high risk factor for spontaneous and often fatal lobar hemorrhage is cerebral amyloid angiopathy (CAA). We now report that CAA in an amyloid precursor protein transgenic mouse model (APP23 mice) leads to a loss of vascular smooth muscle cells, aneurysmal vasodilatation, and in rare cases, vessel obliteration and severe vasculitis. This weakening of the vessel wall is followed by rupture and bleedings that range from multiple, recurrent microhemorrhages to large hematomas. Our results demonstrate that, in APP transgenic mice, the extracellular deposition of neuron-derived beta-amyloid in the vessel wall is the cause of vessel wall disruption, which eventually leads to parenchymal hemorrhage. This first mouse model of CAA-associated hemorrhagic stroke will now allow development of diagnostic and therapeutic strategies.


Subject(s)
Cerebral Amyloid Angiopathy/pathology , Cerebral Hemorrhage/pathology , Aging/pathology , Amyloid beta-Protein Precursor/genetics , Amyloid beta-Protein Precursor/metabolism , Animals , Blood-Brain Barrier , Brain/blood supply , Brain/pathology , Cerebral Amyloid Angiopathy/complications , Cerebral Amyloid Angiopathy/metabolism , Cerebral Hemorrhage/etiology , Cerebral Hemorrhage/metabolism , Disease Models, Animal , Disease Progression , Female , Inbreeding , Male , Mice , Mice, Inbred C57BL , Mice, Transgenic , Muscle, Smooth, Vascular/pathology , Mutation , Reproducibility of Results , Vasculitis, Central Nervous System/complications , Vasculitis, Central Nervous System/pathology , Vasodilation
9.
Ann N Y Acad Sci ; 903: 307-16, 2000 Apr.
Article in English | MEDLINE | ID: mdl-10818520

ABSTRACT

Cerebrovascular deposition of amyloid is a frequent observation in Alzheimer's disease patients. It can also be detected sporadically in normal aged individuals and is further found in familial diseases linked to specific gene mutations. The source and mechanism of this pathology are still unknown. It has been suggested that amyloidogenic proteins are derived from blood, the vessel wall itself, or from the central nervous system. In this article evidence is reviewed for and against each of these hypotheses, including new data obtained from transgenic mouse models. In APP23 transgenic mice that develop cerebral amyloid angiopathy (CAA) in addition to amyloid plaques, the transport and drainage of neuronally produced amyloid-beta (A beta) seem to be responsible for CAA rather than vascular A beta production or blood uptake. Although a number of mechanisms may contribute to CAA in humans, these results suggest that a neuronal source of A beta is sufficient to induce vascular amyloid deposition. The possibility to cross genetically defined mouse models of CAA with other mutant mice now has the potential to identify molecular mechanisms of CAA.


Subject(s)
Alzheimer Disease/physiopathology , Amyloid beta-Peptides/metabolism , Amyloid/metabolism , Cerebral Amyloid Angiopathy/physiopathology , Cerebrovascular Circulation/physiology , Alzheimer Disease/pathology , Animals , Brain/metabolism , Brain/pathology , Disease Models, Animal , Humans , Mice , Mice, Transgenic , Neurons/metabolism
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