Tau expression levels from various adeno‐associated virus vector serotypes produce graded neurodegenerative disease states

Abstract

Neurodegenerative diseases involving neurofibrillary tangle pathology are pernicious. By expressing the microtubule-associated protein tau, a major component of tangles, with a viral vector, we induce neuropathological sequelae in rats that are similar to those seen in human tauopathies. We tested several variants of the adeno-associated virus (AAV) vector for tau expression in the nigrostriatal system in order to develop models with graded onset and completeness. Whereas previous studies with AAV2 tau vectors produced partial lesions of the nigrostriatal system, AAV9 or AAV10 tau vectors were more robust. These vectors had formidable efficacy relative to 6-hydroxydopamine for dopamine loss in the striatum. Time-courses for tau transgene expression, dopamine loss and rotational behavior tracked the disease progression with the AAV9 tau vector. There was a nearly complete lesion over a delayed time-course relative to 6-hydroxydopamine, with a sequence of tau expression by 1 week, dopamine loss by 2 weeks and then behavior effect by 3-4 weeks. Relative to AAV2 or AAV8, tau expression from AAV9 or AAV10 peaked earlier and caused more dopamine loss. Varying vector efficiencies produced graded states of disease up to nearly complete. The disease models stemming from the AAV variants AAV9 or AAV10 may be useful for rapid drug screening, particularly for tau diseases that affect the nigrostriatal system, such as progressive supranuclear palsy.

Dendritic Degeneration, Neurovascular Defects, and Inflammation Precede Neuronal Loss in a Mouse Model for Tau-Mediated Neurodegeneration

“…Early inflammatory response has been suggested to precede neuronal loss in a similar model of AAV9-mediated expression of protein tau in the substantia nigra. 46,47 We extensively probed the mechanisms that activate microglia because they are most closely concerned in the AAV-tau-induced neurodegeneration, corroborating the observations in the cdk5/p25 model for hippocampal sclerosis.…”

AAV9-mediated erythropoietin gene delivery into the brain protects nigral dopaminergic neurons in a rat model of Parkinson's disease

“…The AAV9 vector produced widespread neuronal expression of either EPO or GFP transgenes in the striatum, which recapitulated the high-efficiency neuronal transduction observed previously with this vector in the rat hippocampus or SN. 19,20 The expression seemed to be stable between 3 and 10 weeks after gene transfer. In addition to the widespread striatal transduction, either the expressed EPO or GFP was detected in the SNpr, an anterograde terminal area of striatal output neurons, and for EPO, expression was observed in DA neuronal perikarya in the SNpc.…”

“…TH-IR neurons in the SNpc were examined using unbiased stereology (the MicroBrightfield Inc system, Williston, VT, USA), as described previously. 20 Five sections evenly spaced throughout the rostral SNpc structure (from 5.0 to 6.0 posterior to Bregma) were analyzed for each probe. Optical dissectors were 50 Â 50 Â 16 mm cubes spaced in a systematic random manner 150 Â 150 mm apart and offset 2 mm from the section surface.…”

“…14 Numerous studies have shown that recombinant AAV with newer serotypes have improved gene transfer into the brain. [17][18][19][20] AAV9 vectors are of particular interest because of their high gene transfer efficiency in the brain. [18][19][20] Adeno-associated virus-mediated EPO gene delivery into skeletal muscle has been previously reported to result in sustained EPO gene expression and systemic delivery of therapeutic protein in mice [21][22][23][24] and nonhuman primates.…”

“…[17][18][19][20] AAV9 vectors are of particular interest because of their high gene transfer efficiency in the brain. [18][19][20] Adeno-associated virus-mediated EPO gene delivery into skeletal muscle has been previously reported to result in sustained EPO gene expression and systemic delivery of therapeutic protein in mice [21][22][23][24] and nonhuman primates. [25][26][27][28] However, it is not clear whether AAV-mediated EPO gene delivery into the brain can produce sustained EPO gene expression and elicit functional benefits in an animal model of PD.…”