Abstract
Intraneuronal neurofibrillary tangles (NFTs) – a characteristic pathological feature of Alzheimer’s and several other neurodegenerative diseases – are considered a major target for drug development. Tangle load correlates well with the severity of cognitive symptoms and mouse models of tauopathy are behaviorally impaired. However, there is little evidence that NFTs directly impact physiological properties of host neurons. Here we used a transgenic mouse model of tauopathy to study how advanced tau pathology in different brain regions affects activity-driven expression of immediate-early gene Arc required for experience-dependent consolidation of long-term memories. We demonstrate in vivo that visual cortex neurons with tangles are as likely to express comparable amounts of Arc in response to structured visual stimulation as their neighbors without tangles. Probability of experience-dependent Arc response was not affected by tau tangles in both visual cortex and hippocampal pyramidal neurons as determined postmortem. Moreover, whole brain analysis showed that network-wide activity-driven Arc expression was not affected by tau pathology in any of the brain regions, including brain areas with the highest tangle load. Our findings suggest that intraneuronal NFTs do not affect signaling cascades leading to experience-dependent gene expression required for long-term synaptic plasticity.
Highlights
Intraneuronal neurofibrillary tangles (NFT) composed of misfolded hyperphosphorylated tau proteins are one of two stereotypical types of lesions present in the Alzheimer’s brain [1]
Triple transgenic Arc::dVenus × CamKII::rtTA × tetO::Tau(P301L) (Arc::dVenus × rTg4510) mice of tangle-bearing age (11–12 months old) and littermate Arc::dVenus × CamKII::rtTA controls were housed in light-proof dark enclosures for 60 hours prior to being exposed for 1 hour to structured visual stimulation in a glass cylinder with alternating black and white stripes illuminated from the outside (Figure 1a)
Reporter mice expressing a fluorescent protein under the control of the plasticity-related immediateearly gene Arc promoter [15] were crossed to a model of tauopathy based on P301L mutation in the human tau protein [14]
Summary
Intraneuronal neurofibrillary tangles (NFT) composed of misfolded hyperphosphorylated tau proteins are one of two stereotypical types of lesions present in the Alzheimer’s brain (together with amyloid plaques) [1]. The extent of neurofibrillary pathology correlates well with synaptic loss, neuronal loss, glial activation, and cognitive decline [2] and tangles have long been considered a primary therapeutic target in Alzheimer’s disease (AD). We hypothesized that the tangle pathology would disrupt integration of incoming information in individual neurons with NFTs and that the brain networks most affected by tangles would have impaired neuroplastic properties when responding to sensory inputs in vivo. Activitydriven expression of Arc is crucial for synaptic tagging and remodeling in response to sensory and behavioral inputs (reviewed in [5,6,7,8,9]) and is often used as a reporter of expression of neuroplasticity in excitatory neurons
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