AAV vectors to study the functional consequences of neuronal and astrocytic tau pathology using in vivo 2‐photon imaging

Abstract

AbstractBackgroundTau pathology is a defining histopathological feature of Alzheimer’s disease (AD) and primary tauopathies such as progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). Whereas AD is mostly characterized by neuronal tau pathology, primary tauopathies such as PSP and CBD also present with glial tau pathology. How tau pathology affects the activity of distinct neuronal cell types (e.g. interneurons) or glial cells (e.g. astrocytes) is currently unknown. We have developed adeno‐associated virus (AAV)‐based tauopathy models of neuronal and astrocytic tau pathology to study the functional consequences of tau pathology using in vivo 2‐photon imaging.MethodWe present AAV vectors expressing human truncated tau (amino acids 151‐391/4R) and red fluorophore mCherry in equal ratio under the neuronal human synapsin promotor (AAV‐hSyn‐htTau) or the astrocytic GFAP promotor (AAV‐GFAP‐htTau). AAVs expressing only mCherry under the same promotors were used as controls. AAVs were injected into the hippocampus of wild‐type mice for histological, biochemical, and behavioral characterization.AAV‐hSyn‐htTau was injected intracerebroventricularly in PV‐Cre mice to study the effects of tau pathology on pyramidal neurons or interneurons using in vivo 2‐photon calcium imaging. AAV‐GFAP‐htTau was injected into the cortex of wild‐type or CX3CR1‐YFP mice to study the effects of astrocytic tau pathology on neuronal activity or microglia using in vivo imaging, respectively.ResultAAV‐hSyn‐htTau and AAV‐GFAP‐htTau both induced widespread expression of mCherry and hyperphosphorylated tau in neurons or astrocytes, respectively. Only the neuronal model induced abundant sarkosyl insoluble tau and methoxy‐XO4+ aggregated tau. In vivo 2‐photon calcium imaging of cortical neurons revealed increased spiking activity in truncated tau‐expressing PV+ interneurons, but not in pyramidal cells, suggesting that tau‐mediated alteration of interneuron activity is an early pathological event. No cognitive impairments were detected at early timepoints.Astrocytic tau pathology led to inflammatory changes of blood vessels, such as upregulation of adhesion molecules VCAM1 and ICAM1. No changes in cognition or neuronal spiking activity were detected at the examined timepoints. Analysis of microglial morphology and motility is currently ongoing.ConclusionAAV‐based tauopathy models are attractive tools to study the consequences of neuronal and glial tau pathology in vivo. Funding: VEGA 2/0135/18 and SyDAD (Horizon 2020, 676144)