Summary The spread of protein aggregates during disease progression is a common theme underlying many neurodegenerative diseases. The microtubule-associated protein tau (MAPT) plays a central role in the pathogenesis of several forms of dementia known as tauopathies, including Alzheimer’s disease (AD), frontotemporal dementia (FTD) and chronic traumatic encephalopathy (CTE) 1 . Progression of these diseases is characterized by the sequential spread and deposition of protein aggregates in a predictable pattern that correlates with clinical severity 2 . This observation and complementary experimental studies 3 , 4 have suggested that tau can spread in a prion-like manner by passing to naïve cells where it templates misfolding and aggregation. However, while tau propagation has been extensively studied, the underlying cellular mechanisms remain poorly understood. Here we show that the low-density lipoprotein (LDL) receptor-related protein 1 (LRP1) controls tau endocytosis and subsequent spread. Knockdown of LRP1 significantly reduced tau uptake in H4 neuroglioma cells and iPS-derived neurons. The interaction between tau and LRP1 is mediated by lysine residues in the microtubule binding repeat region of tau. Furthermore, we find that downregulation of LRP1 in an in vivo mouse model of tau spread effectively reduced tau propagation between neurons. Our results identify LRP1 as a key regulator of tau spread in the brain and, thus, as a novel target for diseases of tau spread and aggregation.

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Tau inclusions are a shared feature of many neurodegenerative diseases, among them frontotemporal dementia caused by tau mutations. Treatment approaches for these conditions include targeting posttranslational modifications of tau proteins, maintaining a steady-state amount of tau, and preventing its tendency to aggregate. We discovered a new regulatory pathway for tau degradation that operates through the farnesylated protein, Rhes, a GTPase in the Ras family. Here, we show that treatment with the farnesyltransferase inhibitor lonafarnib reduced Rhes and decreased brain atrophy, tau inclusions, tau sumoylation, and tau ubiquitination in the rTg4510 mouse model of tauopathy. In addition, lonafarnib treatment attenuated behavioral abnormalities in rTg4510 mice and reduced microgliosis in mouse brain. Direct reduction of Rhes in the rTg4510 mouse by siRNA reproduced the results observed with lonafarnib treatment. The mechanism of lonafarnib action mediated by Rhes to reduce tau pathology was shown to operate through activation of lysosomes. We finally showed in mouse brain and in human induced pluripotent stem cell–derived neurons a normal developmental increase in Rhes that was initially suppressed by tau mutations. The known safety of lonafarnib revealed in human clinical trials for cancer suggests that this drug could be repurposed for treating tauopathies.

PURPOSE. We determined the time lag between loss of retinal ganglion cell function and retinal nerve fiber layer (RNFL) thickness.METHODS. Glaucoma suspects were followed for at least four years. Patients underwent pattern electroretinography (PERG), optical coherence tomography (OCT) of the RNFL, and standard automated perimetry testing at 6-month intervals. Comparisons were made between changes in all testing modalities. To compare PERG and OCT measurements on a normalized scale, we calculated the dynamic range of PERG amplitude and RNFL thickness. The time lag between function and structure was defined as the difference in time-to-criterion loss between PERG amplitude and RNFL thickness.RESULTS. For PERG (P < 0.001) and RNFL (P ¼ 0.030), there was a statistically significant difference between the slopes corresponding to the lowest baseline PERG amplitude stratum ( 50%) and the reference stratum (>90%). Post hoc comparisons demonstrated highly significant differences between RNFL thicknesses of eyes in the stratum with most severely affected PERG ( 50%) and the two strata with least affected PERG (>70%). Estimates suggested that the PERG amplitude takes 1.9 to 2.5 years to lose 10% of its initial amplitude, whereas the RNFL thickness takes 9.9 to 10.4 years to lose 10% of its initial thickness. Thus, the time lag between PERG amplitude and RNFL thickness to lose 10% of their initial values is on the order of 8 years.CONCLUSIONS. In patients who are glaucoma suspects, PERG signal anticipates an equivalent loss of OCT signal by several years. (Invest Ophthalmol Vis Sci. 2013;54:2346-2352 DOI: 10.1167/iovs.12-11026 A n issue central to the treatment of glaucoma is determining the onset of the disease. The current understanding is that early signs of glaucoma often manifest as permanent atrophic changes in the optic nerve, which are detected by characteristic visual field defects. Structural changes can be observed directly by examining the optic nerve, but also by measuring the optic nerve and retinal nerve fiber layer (RNFL) thickness with imaging devices. It is likely that these clinically manifest structural-functional changes are preceded by subclinical stages, at which retinal ganglion cells (RGC) have lost their autoregulatory ability in response to a chronically stressful biomechanical, vascular, or molecular environment, and become increasingly dysfunctional over time until they die and are eliminated from the neuronal pool.1 The transition between normal and abnormal homeostasis may be considered the true time of disease onset, whereas the stage of RGC dysfunction preceding death represents the ideal stage during which therapeutic strategies to prevent cell death and visual loss should be initiated.The electrical responsiveness of RGC to contrast-reversing visual stimuli can be monitored noninvasively in human and experimental models of glaucoma with the pattern electroretinogram (PERG).2-7 Recent studies in human and mouse models of glaucoma have shown that in the early stages of the disease the m...

Müller cells are subtly different in the GFAP(-/-)vim(-/-) mouse retina before detachment. The end foot region of these cells may be structurally reinforced by the presence of the intermediate filament cytoskeleton, and our data suggest a critical role for these proteins in Müller cell reaction to retinal detachment and participation in subretinal gliosis.