Neurofibrillary tangle-bearing neurons are functionally integrated in cortical circuits in vivo

Abstract

Alzheimer's disease (AD) is pathologically characterized by the deposition of extracellular amyloid-β plaques and intracellular aggregation of tau protein in neurofibrillary tangles (NFTs) (1, 2). Progression of NFT pathology is closely correlated with both increased neurodegeneration and cognitive decline in AD (3) and other tauopathies, such as frontotemporal dementia (4,5). The assumption that mislocalization of tau into the somatodendritic compartment (6) and accumulation of fibrillar aggregates in NFTs mediates neurodegeneration underlies most current therapeutic strategies aimed at preventing NFT formation or disrupting existing NFTs (7,8). Although several disease-associated mutations cause both aggregation of tau and neurodegeneration, whether NFTs per se contribute to neuronal and network dysfunction in vivo is unknown (9). Here we used awake in vivo two-photon calcium imaging to monitor neuronal function in adult rTg4510 mice that overexpress a human mutant form of tau (P301L) and develop cortical NFTs by the age of 7-8 mo (10). Unexpectedly, NFT-bearing neurons in the visual cortex appeared to be completely functionally intact, to be capable of integrating dendritic inputs and effectively encoding orientation and direction selectivity, and to have a stable baseline resting calcium level. These results suggest a reevaluation of the common assumption that insoluble tau aggregates are sufficient to disrupt neuronal function.paired helical filaments | tau pathology | neuronal networks N eurofibrillary tangles (NFTs) containing aggregated tau protein (1) have long been considered key players in the progressive neural dysfunction and neurodegeneration observed in Alzheimer's disease (AD) (2, 3) and other tauopathies (4, 5). It is commonly assumed that NFT-bearing neurons exhibit deficits in synaptic integration and eventually lead to neurodegeneration (11,12). However, the actual functional properties of NFT-bearing neurons in intact neural circuits have not been explored previously (13). We addressed this question directly using awake in vivo two-photon calcium imaging in a mouse model of NFT formation (rTg4510) by applying recently developed imaging approaches allowing for single-neuron-level and population-level assessment of neural activity in awake mice (14). Because two-photon calcium imaging allows for measurement of response properties in many neurons simultaneously, we were able to directly isolate the impact of NFT deposition in a neuronal microcircuit by evaluating population-level network dynamics and, more specifically, by differentiating the function of individual NFT-bearing and neighboring non-NFT-bearing neurons.To assess the functional properties of neurons in the visual cortex, we used a genetically encoded ratiometric calcium indicator, yellow cameleon 3.6 (YC3.6), packaged in an adenoassociated viral vector (15,16). To assess functional responses, we exploited the well-characterized functional architecture of visual cortex whereby neurons in mouse visual cortex modulate their activity d...

The Intersection of Amyloid Beta and Tau at Synapses in Alzheimer’s Disease

“…Using in vivo multiphoton imaging, we observed that tau-associated dendritic spine loss in the rTg4510 mouse model is not associated with chronically increased resting calcium levels, nor does tau overexpression impair calcium responses to visual stimulation, indicating that pathological forms of tau can cause synapse collapse in a pathway independent of calcium (Kopeikina et al, 2013; Kuchibhotla et al, 2013). This would support a model in which alterations in tau were downstream of increased calcium levels induced by Aβ, but further studies are needed to confirm.…”

Selective degeneration of a physiological subtype of spinal motor neuron in mice with SOD1-linked ALS

“…S7). Surprisingly, many neurons with large intracellular aggregates were capable of being filled via retrograde tracing, indicating that cells with large intracellular SOD1YFP aggregates are still at least partially innervating their target muscle (25). It thus appears that the process of aggregate formation occurs, at least in many cases, before complete denervation at the neuromuscular junction.…”

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“…In all likelihood, none of these algorithms will be adequate to fully address the needs for cell sorting imposed by the large-scale Ca 2+ imaging data sets containing ~10 3 –10 5 individual neurons that are now emerging (see Outlook) (Alivisatos et al, 2013; BRAIN Initiative, 2014; Freeman et al, 2014). One widespread and elementary method for separating signals from different cells is to demarcate the boundaries of individual cells and denote each enclosed area as a region of interest (ROI), one for each cell (Dombeck et al, 2007; Göbel et al, 2007; Kerr et al, 2005; Kuchibhotla et al, 2014; Lovett-Barron et al, 2014; Ozden et al, 2008; Peters et al, 2014). …”