Apolipoprotein E isoform does not influence trans-synaptic spread of tau pathology in a mouse model.

A key hallmark of Alzheimer's disease (AD) is the accumulation of hyperphosphorylated tau in neurofibrillary tangles. This occurs alongside neuroinflammation and neurodegeneration. Pathological tau propagates through the AD brain in a defined manner, which correlates with neuron and synapse loss and cognitive decline. One proposed mechanism of tau spread is through synaptically connected brain structures. Apolipoprotein E4 (APOE4) genotype is the strongest genetic risk factor for late-onset AD and is associated with increased tau burden. Whether the apolipoprotein E (APOE) genotype influences neurodegeneration via tau spread is currently unknown. Here, we demonstrate that virally expressed human tau (with the P301L mutation) injected into mouse entorhinal cortex at 5-6 months or 15-16 months of age spreads trans-synaptically to the hippocampus by 14 weeks post-injection. Injections of tau in mice expressing human APOE2, APOE3 or APOE4, as well as APOE knock-outs, showed that tau can spread trans-synaptically in all genotypes and that APOE genotype and age do not affect the spread of tau. These data suggest that APOE genotype is not directly linked to synaptic spread of tau in our model, but other mechanisms involving non-cell autonomous manners of tau spread are still possible.

Effects of a 12-week, seated, virtual, home-based tele-exercise programme compared with a prerecorded video-based exercise programme in people with chronic neurological impairments: protocol for a randomised controlled trial.

INTRODUCTION: Exercise is vital to staying well and preventing secondary complications in people with chronic neurological impairments (CNI). Appropriate exercise is often inaccessible to this population. The purpose of the study is to investigate the effects of a seated, virtual exercise programme on heart rate, recovery, fatigue, pain, motivation, enjoyment and quality of life in people with CNI. METHODS AND ANALYSIS: Individuals with CNI will be screened for eligibility, and 60 participants will be randomised 1:1 into either a live or prerecorded group. There is no geographical limitation to where participants reside, since participation is virtual. The study will be coordinated by one site in White Plains, New York, USA. The live group will exercise with an instructor via Zoom while the prerecorded group will exercise at their chosen time using prerecorded videos, 3×/week for 12 weeks. PRIMARY OUTCOME MEASURES: change in heart rate during exercise/recovery. SECONDARY OUTCOME MEASURES: fatigue, motivation, level of pain and exertion, physical well-being, enjoyment of physical activity, motivation and quality of life. Outcomes will be assessed at baseline, midpoint, end of study and 1-month poststudy. Adverse events, medication changes and physical activity will be tracked throughout. Within-group and between-group comparisons will be performed by using analysis of covariance and regression. ETHICS AND DISSEMINATION: BRANY IRB approval: 22 September 2020, protocol #20-08-388-512. All participants will provide written informed consent. Results will be disseminated through presentations, publications and ClinicalTrials.gov. TRIAL REGISTRATION NUMBER: NCT04564495.