Immunolesion-induced loss of cholinergic projection neurones promotes ß-amyloidosis and tau hyperphosphorylation in the hippocampus of triple-transgenic mice.

AIMS: Currently available animal models incompletely capture the complex pathophysiology of Alzheimer's disease (AD), typically involving ß-amyloidosis, neurofibrillary tangle formation and loss of basal forebrain cholinergic projection neurones (CPN). While age-dependent ß-amyloidosis and tau hyperphosphorylation are mimicked in triple-transgenic mice (3xTg), experimental induction of CPN loss in these mice is still lacking. Here, we introduce a more-complex animal model of AD by inducing cellular loss of CPN in an already existing transgenic background aiming to elucidate subsequent changes of hippocampal ß-amyloid (Aß) and tau pathology. METHODS: Twelve-month-old 3xTg mice intracerebroventricularly received the rabbit-anti-low affinity neurotrophin receptor p75-saporin, an immunotoxin specifically targeting forebrain CPN. After histochemical verification of immunolesion in immersion-fixed forebrains, markers of Aß and tau metabolism were analysed using quantitative Western blot analyses of hippocampi from these mice. In parallel, these markers and glial activation were investigated by multiple immunofluorescence labelling of perfusion-fixed hippocampi and confocal laser-scanning microscopy. RESULTS: Four months after immunolesion, the selective lesion of CPN was verified by disappearance of choline acetyltransferase and p75 immunolabelling. Biochemical analysis of hippocampi from immunolesioned mice revealed enhanced levels of Aß, amyloid precursor protein (APP) and its fragment C99. Furthermore, immunolesion-induced increase in levels of phospho-tau and tau with AD-like conformation were seen in 16-month-old mice. Immunofluorescence staining confirmed an age-dependent occurrence of hippocampal Aß-deposits and phospho-tau, and demonstrated drastic gliosis around Aß-plaques after immunolesion. CONCLUSION: Overall, this extended model promises further insights into the complexity of AD and contributes to novel treatment strategies also targeting the cholinergic system.

Predicting intracerebral hemorrhage by baseline magnetic resonance imaging in stroke patients undergoing systemic thrombolysis.

OBJECTIVES: Intracerebral hemorrhage (ICH) remains a serious complication in ischemic stroke patients undergoing systemic thrombolysis. Here, we examined whether the risk of treatment-associated hemorrhage can be predicted from magnetic resonance imaging (MRI) using fluid-attenuated inversion recovery (FLAIR) and diffusion-weighted imaging (DWI) within 3 h after symptom onset. METHODS: In this single-center observational study involving 122 ischemic stroke patients between January 2005 and December 2008, the incidence of FLAIR-positive lesions within diffusion-restricted areas was determined on baseline MRI, which was carried out prior to treatment with tissue plasminogen activator (Actilyse(®) ) within 3 h from symptom onset. The rate of ICH was assessed by computed tomography performed within 24 h after treatment. Relationships between FLAIR-positive lesions, DWI lesion size, proportion of FLAIR/DWI-positive lesions, and occurrence of bleeding were explored. RESULTS: Data from 97 patients were evaluated. FLAIR-positive lesions were present in 25 patients (25.8%) and ICH occurred in 32 patients (33.0%). FLAIR-positive lesions were associated with a bleeding rate of 80.0% compared with 16.7% in FLAIR-negative patients (P < 0.001; odds ratio 20.0, positive predictive value 0.8). DWI lesion size was significantly correlated with the rate of ICH (P = 0.001). In contrast, FLAIR/DWI proportion was not associated with ICH (P = 0.788). CONCLUSIONS: In ischemic stroke patients within 3 h from symptom onset, the existence of FLAIR-positive lesions on pretreatment MRI is significantly associated with an increased bleeding risk due to systemic thrombolysis. Therefore, considering FLAIR-positive lesions on baseline MRI might guide treatment decisions in ischemic stroke.