Alzheimer's disease protease-containing plasma extracellular vesicles transfer to the hippocampus via the choroid plexus.

BACKGROUND: Plasma extracellular vesicles (pEV) can harbor a diverse array of factors including active proteases and the amyloid-precursor-protein (APP) cleavage product Aß, involved in plaque formation in Alzheimer`s diseases (AD). A potential role of such vesicles in AD pathology is unexplored. METHODS: In a case-control study of randomly selected patients with AD and other neurological diseases (n = 14), and healthy controls (n = 7), we systematically analyzed the content of pEV, using different assay systems. In addition, we determined their entry path into brain tissue, employing animal (mice) injection experiments with ex vivo generated EV that were similar to AD-pEV, followed by multi antigen analysis (MAA) of brain tissue (n = 4 per condition). The results were compared with an IHC staining of human brain tissue in a small cohort of AD patients (n = 3) and controls with no neurodegenerative diseases (n = 3). FINDINGS: We show that pEV levels are considerably upregulated in AD patients. Besides numerous inflammatory effectors, AD-pEV contained α-, ß- and γ-secretases, able to cleave APP in in target cells. In vitro generated EV with similar characteristics as AD-pEV accumulated in the choroid plexus (CP) of injected animals and reached primarily hippocampal neurons. Corroborating findings were made in human brain samples. An inhibitor of hyaluronic-acid-synthetase (HAS) blocked uploading of proteases and Hyaluronan onto EV in vitro and abolished CP targeting in animal injection experiments. INTERPRETATION: We conclude that protease-containing pEV could be part of a communication axis between the periphery and the brain that could be become detrimental depending on pEV concentration and duration of target cell impact. FUNDING: See the Acknowledgements section.

Atrophy in the Thalamus But Not Cerebellum Is Specific for C9orf72 FTD and ALS Patients - An Atlas-Based Volumetric MRI Study.

Background: The neuropathology of patients with frontotemporal dementia (FTD) or amyotrophic lateral sclerosis (ALS) due to a C9orf72 mutation is characterized by two distinct types of characteristic protein depositions containing either TDP-43 or so-called dipeptide repeat proteins that extend beyond frontal and temporal regions. Thalamus and cerebellum seem to be preferentially affected by the dipeptide repeat pathology unique to C9orf72 mutation carriers. Objective: This study aimed to determine if mutation carriers showed an enhanced degree of thalamic and cerebellar atrophy compared to sporadic patients or healthy controls. Methods: Atlas-based volumetry was performed in 13 affected C9orf72 FTD, ALS and FTD/ALS patients, 45 sporadic FTD and FTD/ALS patients and 19 healthy controls. Volumes and laterality indices showing significant differences between mutation carriers and sporadic patients were subjected to binary logistic regression to determine the best predictor of mutation carrier status. Results: Compared to sporadic patients, mutation carriers showed a significant volume reduction of the thalamus, which was most striking in the occipital, temporal and prefrontal subregion of the thalamus. Disease severity measured by mini mental status examination (MMSE) and FTD modified Clinical Dementia Rating Scale Sum of Boxes (FTD-CDR-SOB) significantly correlated with volume reduction in the aforementioned thalamic subregions. No significant atrophy of cerebellar regions could be detected. A logistic regression model using the volume of the prefrontal and the laterality index of the occipital subregion of the thalamus as predictor variables resulted in an area under the curve (AUC) of 0.88 while a model using overall thalamic volume still resulted in an AUC of 0.82. Conclusion: Our data show that thalamic atrophy in C9orf72 mutation carriers goes beyond the expected atrophy in the prefrontal and temporal subregion and is in good agreement with the cortical atrophy pattern described in C9orf72 mutation carriers, indicating a retrograde degeneration of functionally connected regions. Clinical relevance of the detected thalamic atrophy is illustrated by a correlation with disease severity. Furthermore, the findings suggest MRI volumetry of the thalamus to be of high predictive value in differentiating C9orf72 mutation carriers from patients with sporadic FTD.

Beta-amyloid peptides in cerebrospinal fluid of patients with Creutzfeldt-Jakob disease.

Decreased levels of beta-amyloid peptide 1-42 (Abeta1-42) in cerebrospinal fluid (CSF) are a characteristic feature of Alzheimer's disease (AD) but recently were also observed in Creutzfeldt-Jakob disease (CJD). We analyzed the CSF of patients with CJD, and AD and nondemented controls using a quantitative urea-based Abeta sodium dodecyl sulfate polyacrylamide gel electrophoresis immunoblot. Like in AD and nondemented controls, we found a highly conserved pattern of carboxyterminally truncated Abeta1-37/38/39 in addition to Abeta1-40/42 also in CJD patients. By the introduction of the ratio Abeta1-39 to Abeta1-42, CJD and AD can effectively be differentiated. We conclude that the immunoblot shows disease-specific CSF Abeta peptide patterns in CJD and AD and suppose that measurement of the Abeta peptide pattern seems to be a promising diagnostic tool in the differential diagnosis of dementias.