Acta Neuropathologica Communications最新文献

Mutations in the presenilin (PS/PSEN) genes cause early-onset familial Alzheimer's disease (AD) by enhancing cerebral accumulation of amyloid-β (Aβ) peptides and microtubule-associated protein tau (MAPT). How PS mutations affect Aβ generation is well characterized, but the precise cellular mechanisms by which PS dysfunction drives neuronal tau pathology are not fully understood. Here, we investigated the mechanisms linking PS/γ-secretase-dependent tau pathology and autophagy/proteasome by employing pathological, imaging and molecular approaches in human brains, fibroblasts and induced pluripotent stem cells (iPSC)-derived neurons from PSEN1-linked familial AD carriers, and in a novel neuronal PS-deficient tauopathy transgenic mouse. We found enhanced levels and colocalization of pathological phosphorylated tau (pTau) and ubiquitin factor p62 in the hippocampus of dementia patients with familial AD-linked PSEN1 mutations, corticobasal degeneration and Pick's disease, suggesting disrupted proteasomal degradation in tauopathies. Human primary fibroblasts from PSEN1 G206D and/or L286P carriers showed elevated LC3-I and autolysosomes indicating autophagy flux alterations. Human iPSC-derived neurons harboring the familial-AD linked PSEN1 G206D mutation showed increased aggregated tau and reduced secreted tau, whereas pharmacological proteasome inhibition reduced significantly total and pTau (Ser396/404) while increasing its release. Consistently, proteasomal inhibition decreased intracellular tau and pTau and promoted tau release in human tau-expressing neurons through a mechanism that partially depends on PS. In the hippocampus of neuronal PS-deficient mice, Akt activation and GSK3β inhibition were associated with elevated levels of phosphorylated and aggregated tau and the ubiquitin-binding protein p62. In conclusion, PS function is required for autophagy/proteasome-mediated tau elimination in neurons, whereas that FAD-linked PSEN1 mutations cause progressive tau pathology by disrupting the proteasome and autophagy/lysosomal pathways.

Carotid artery disease (CAD) is a recognised cause of stroke. However, the relationships between CAD, cerebral small vessel disease (SVD) and dementia remain unclear. We hypothesised that CAD in older individuals contributes to cerebral SVD pathology by altering cerebral perfusion. We performed a clinicopathological study in patients from the Cognitive Function After Stroke (CogFAST) study and prospectively recruited patients with various dementia diagnoses and evidence of cerebral SVD. In addition to brain tissues, we collected postmortem samples of the internal carotid arteries (ICA) from these cohorts in the Newcastle Brain Tissue Resource. Standard neuropathological examination was performed for diagnosis and assignment of the cases per current diagnostic criteria for vascular and neurodegenerative dementias, which were assessed for the presence of vascular pathology including the degree of stenosis and sclerosis in vascular tissues. We evaluated a total of 159 ICA samples and brain tissues from all cases with evidence of SVD. Severity of ICA stenosis and sclerotic index correlated strongly with both clinical stroke and brain infarction (P < 0.001). More than 90% of the subjects had one subtype of ICA lesion in the order: intimal thickening > fibrocalcific > fibrous cap (thick) > fibrous cap (thin) > thrombus group with a strong inflammatory reaction in fibrocalcific atheromas. Regression analyses showed that ICA stenosis was positively correlated to both SVD pathology scores (P < 0.034) and the total number of vascular lesions (P < 0.001). ICA stenosis was also related to dementia caused by cerebrovascular disease (P < 0.001) and by mixed pathologies characterised by Alzheimer's disease and SVD (P = 0.025). Severity of stenosis was related to subcortical and white matter (WM) vascular lesions within the anterior circulation. ICA stenosis and sclerosis were moreover correlated with the total intracranial artery pathology scores (P < 0.001). In the CogFAST group analysis, we observed that MMSE and CAMCOG scores were lower in subjects with moderate to severe stenosis scores compared to the mild stenosis group (P < 0.05). In these CogFAST cases, by far the majority of lesions in the WM were small in size (< 5 mm, range 72-91%) but not in the cortex or basal ganglia and thalamus. Linear regression analysis further indicated that there were greater numbers of these small lesions in the WM with increasing severity of ICA stenosis (P < 0.05). Our observations suggest carotid atherosclerosis promotes cerebral SVD types of change within the intracerebral arteries. It is conceivable that extracranial ICA pathology may influence perfusion and integrity of subcortical structures including the deep WM.