Person:

Wegmann, Susanne

Abstract Alzheimer's disease is characterized by the presence of aggregates of amyloid beta (Aβ) in senile plaques and tau in neurofibrillary tangles, as well as marked neuron and synapse loss. Of these pathological changes, synapse loss correlates most strongly with cognitive decline. Synapse loss occurs prominently around plaques due to accumulations of oligomeric Aβ. Recent evidence suggests that tau may also play a role in synapse loss but the interactions of Aβ and tau in synapse loss remain to be determined. In this study, we generated a novel transgenic mouse line, the APP/PS1/rTg21221 line, by crossing APP/PS1 mice, which develop Aβ‐plaques and synapse loss, with rTg21221 mice, which overexpress wild‐type human tau. When compared to the APP/PS1 mice without human tau, the cross‐sectional area of ThioS+ dense core plaques was increased by ~50%. Along with increased plaque size, we observed an increase in plaque‐associated dystrophic neurites containing misfolded tau, but there was no exacerbation of neurite curvature or local neuron loss around plaques. Array tomography analysis similarly revealed no worsening of synapse loss around plaques, and no change in the accumulation of Aβ at synapses. Together, these results indicate that adding human wild‐type tau exacerbates plaque pathology and neurite deformation but does not exacerbate plaque‐associated synapse loss.

Abstract The transition between soluble intrinsically disordered tau protein and aggregated tau in neurofibrillary tangles in Alzheimer's disease is unknown. Here, we propose that soluble tau species can undergo liquid–liquid phase separation (LLPS) under cellular conditions and that phase‐separated tau droplets can serve as an intermediate toward tau aggregate formation. We demonstrate that phosphorylated or mutant aggregation prone recombinant tau undergoes LLPS, as does high molecular weight soluble phospho‐tau isolated from human Alzheimer brain. Droplet‐like tau can also be observed in neurons and other cells. We found that tau droplets become gel‐like in minutes, and over days start to spontaneously form thioflavin‐S‐positive tau aggregates that are competent of seeding cellular tau aggregation. Since analogous LLPS observations have been made for FUS, hnRNPA1, and TDP43, which aggregate in the context of amyotrophic lateral sclerosis, we suggest that LLPS represents a biophysical process with a role in multiple different neurodegenerative diseases.

Abstract Synaptic dysfunction and loss is the strongest pathological correlate of cognitive decline in Alzheimer's disease (AD) with increasing evidence implicating neuropathological tau protein in this process. Despite the knowledge that tau spreads through defined synaptic circuits, it is currently unknown whether synapse loss occurs before the accumulation of tau or as a consequence. To address this, we have used array tomography to examine an rTgTauEC mouse model expressing a P301L human tau transgene and a transgene labeling cytoplasm red (tdTomato) and presynaptic terminals green (Synaptophysin‐EGFP). All transgenes are restricted primarily to the entorhinal cortex using the neuropsin promotor to drive tTA expression. It has previously been shown that rTgTauEC mice exhibit neuronal loss in the entorhinal cortex and synapse density loss in the middle molecular layer (MML) of the dentate gyrus at 24 months of age. Here, we observed the density of tau‐expressing and total presynapses, and the spread of tau into the postsynapse in the MML of 3–6, 9, and 18 month old red–green‐rTgTauEC mice. We observe no loss of synapse density in the MML up to 18 months even in axons expressing tau. Despite the maintenance of synapse density, we see spread of human tau from presynaptic terminals to postsynaptic compartments in the MML at very early ages, indicating that the spread of tau through neural circuits is not due to the degeneration of axon terminals and is an early feature of the disease process.