Cardiac ATTR amyloidosis, a serious but much under-diagnosed form of cardiomyopathy, is caused by deposition of amyloid fibrils derived from the plasma protein transthyretin (TTR), but its ...pathogenesis is poorly understood and informative in vivo models have proved elusive. Here we report the generation of a mouse model of cardiac ATTR amyloidosis with transgenic expression of human TTR
. The model is characterised by substantial ATTR amyloid deposits in the heart and tongue. The amyloid fibrils contain both full-length human TTR protomers and the residue 49-127 cleavage fragment which are present in ATTR amyloidosis patients. Urokinase-type plasminogen activator (uPA) and plasmin are abundant within the cardiac and lingual amyloid deposits, which contain marked serine protease activity; knockout of α
-antiplasmin, the physiological inhibitor of plasmin, enhances amyloid formation. Together, these findings indicate that cardiac ATTR amyloid deposition involves local uPA-mediated generation of plasmin and cleavage of TTR, consistent with the previously described mechano-enzymatic hypothesis for cardiac ATTR amyloid formation. This experimental model of ATTR cardiomyopathy has potential to allow further investigations of the factors that influence human ATTR amyloid deposition and the development of new treatments.
The CA2 region of the mammalian hippocampus is a unique region with its own distinctive properties, inputs and pathologies. Disruption of inhibitory circuits in this region appears to be linked with ...the pathology of specific psychiatric disorders, promoting interest in its local circuitry, its role in hippocampal function and its dysfunction in disease. In previous studies, CA2 interneurons, including a novel subclass of CA2 dendrite-preferring interneurons that has not been identified in other CA regions, have been shown to display physiological, synaptic and morphological properties unique to this sub-field and may therefore play a crucial role in the hippocampal circuitry. The distributions of immuno-labeled interneurons in dorsal CA2 were studied and compared with those of interneurons in CA1 and CA3. Like those in CA1 and CA3, the somata of CA2 parvalbumin-immunoperoxidase-labeled interneurons were located primarily in Stratum Pyramidale (SP) and Stratum Oriens (SO), with very few cells in Stratum Radiatum (SR) and none in Stratum Lacunosum Moleculare (SLM). There was, however, a greater proportion of GAD-positive cells were immunopositive for PV in SP in CA2 than in CA1 or CA3. CA2 SP also contained a larger density of somatostatin-, calbindin-, and VIP-immunopositive somata than CA1 and/or CA3. Like those in CA1 and CA3, CCK-immunopositive somata in CA2 were mostly located in SR. Reelin- and NPY- immunolabeled cell bodies were located in all layers of the three CA regions. However, a higher density of Reelin-positive somata was found in SP and SR of CA2 than in CA1 or CA3.
The investigators describe antibodies that bound amyloid in three patients with transthyretin amyloidosis. Spontaneous regression of cardiomyopathy occurred in all three patients.
Systemic amyloidosis is a serious disease which is caused when normal circulating proteins misfold and aggregate extracellularly as insoluble fibrillary deposits throughout the body. This commonly ...results in cardiac, renal and neurological damage. The tissue target, progression and outcome of the disease depends on the type of protein forming the fibril deposit, and its correct identification is central to determining therapy. Proteomics is now used routinely in our centre to type amyloid; over the past 7 years we have examined over 2000 clinical samples. Proteomics results are linked directly to our patient database using a simple algorithm to automatically highlight the most likely amyloidogenic protein. Whilst the approach has proved very successful, we have encountered a number of challenges, including poor sample recovery, limited enzymatic digestion, the presence of multiple amyloidogenic proteins and the identification of pathogenic variants. Our proteomics procedures and approaches to resolving difficult issues are outlined.
The CA2 region of the mammalian hippocampus is a unique region with its own distinctive properties, inputs and pathologies. Disruption of inhibitory circuits in this region appears to be linked with ...the pathology of specific psychiatric disorders, promoting interest in its local circuitry, its role in hippocampal function and its dysfunction in disease. In previous studies, CA2 interneurones, including a novel subclass of CA2 dendrite-preferring interneurones that has not been identified in other CA regions, have been shown to display physiological, synaptic and morphological properties unique to this sub-field and may therefore play a crucial role in the hippocampal circuitry. The distributions of immuno-labelled interneurones in dorsal CA2 were studied and compared with those of interneurones in CA1 and CA3. Like those in CA1 and CA3, the somata of CA2 parvalbumin-immunoperoxidase-labeled interneurones were located primarily in Stratum Pyramidale (SP) and Stratum Oriens (SO), with very few cells in Stratum Radiatum (SR) and none in Stratum Lacunosum Moleculare (SLM). There was, however, a greater proportion of GAD-positive cells were immunopositive for PV in SP in CA2 than in CA1 or CA3. CA2 SP also contained a larger density of somatostatin-, calbindin- and VIP-immunopositive somata than CA1 and/or CA3. Like those in CA1 and CA3, CCK-immunopositive somata in CA2 were mostly located in SR. Reelin- and NPY- immunolabelled cell bodies were located in all layers of the three CA regions. However, a higher density of Reelin-positive somata was found in SP and SR of CA2 than in CA1 or CA3.
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