Human wildtype tau expression in cholinergic pedunculopontine tegmental neurons is sufficient to produce PSP‐like behavioural deficits and neuropathology

• Published in: The European journal of neuroscience 2021-11, Vol.54 (10), p.7688-7709
• Main Authors: King, Gabriella, Veros, Kaliana M., MacLaren, Duncan Archibald Allan, Leigh, Martin Peter Konrad, Spernyak, Joseph A., Clark, Stewart D.
• Format: Article
• Language: English
• Subjects: AAV; acoustic startle; Alzheimer's disease; Animal models; Animals; Autopsy; Basal ganglia; Central nervous system diseases; Cholinergic Agents; Cholinergic Neurons - metabolism; Dementia disorders; Dopamine receptors; Drug therapy; Executive function; Hindbrain; Humans; motor deficit; Movement disorders; MRI; Nervous System Diseases; Neurodegenerative diseases; Neurons; Paralysis; Parkinson's disease; Pathology; Pedunculopontine tegmental nucleus; Progressive supranuclear palsy; Rats; Startle response; Substantia nigra; Supranuclear Palsy, Progressive - genetics; Tau protein; tau Proteins - genetics; tau Proteins - metabolism; tauopathy; Tegmentum; Tegmentum Mesencephali - metabolism
• ISSN: 0953-816X; 1460-9568
• DOI: 10.1111/ejn.15496

Progressive Supranuclear Palsy (PSP) is the most common atypical parkinsonism and exhibits hallmark symptomology including motor function impairment and dysexecutive dementia. In contrast to Parkinson's disease, the underlying pathology displays aggregation of the protein tau, which is also seen in disorders such as Alzheimer's disease. Currently, there are no pharmacological treatments for PSP, and drug discovery efforts are hindered by the lack of an animal model specific to PSP. Based on previous results and clinical pathology, it was hypothesized that viral deposition of tau in cholinergic neurons within the hindbrain would produce a tauopathy along neural connections to produce PSP‐like symptomology and pathology. By using a combination of ChAT‐CRE rats and CRE‐dependent AAV vectors, wildtype human tau (the PSP‐relevant 1N4R isoform; hTau) was expressed in hindbrain cholinergic neurons. Compared to control subjects (GFP), rats with tau expression displayed deficits in a variety of behavioural paradigms: acoustic startle reflex, marble burying, horizontal ladder and hindlimb motor reflex. Postmortem, the hTau rats had significantly reduced number of cholinergic pedunculopontine tegmentum and dopaminergic substantia nigra neurons, as well as abnormal tau deposits. This preclinical model has multiple points of convergence with the clinical features of PSP, some of which distinguish between PSP and Parkinson's disease. Cre‐dependent AAV constructs expressing either GFP or hTau was injected into the PPT of ChAT‐CRE rats (A‐B). Within weeks, the hTau expressing group showed significant behavioural deficits (C; motor—horizontal ladder) and tau pathology (D; AT8) that are consistent with PSP.