Tau is one of the few proteins in the body capable of becoming altered in ways that form harmful aggregates, capable of disrupting cell function or killing cells. Tau aggregation occurs in the aging brain, and particularly in the class of neurodegenerative conditions known as tauopathies. It is tau aggregation that is thought to cause widespread cell death in the late stages of Alzheimer's disease. Researchers here demonstrate a gene therapy approach to significantly reduce tau expression in the brain, a potential basis for long-lasting effects on Alzheimer's disease.
The microtubule-binding protein tau is a key player in Alzheimer's disease (AD) and frontotemporal dementia. The accumulation and aggregation of tau in the brain correlate with synaptic loss, neuronal loss, and cognitive decline. In patients with frontotemporal dementia, mutations in the tau gene, MAPT, lead to tau aggregation and cause widespread neurodegeneration. In addition to the neurotoxicity exerted by aggregated tau, soluble oligomeric forms of tau appear to be especially synaptotoxic.
Mice engineered to lack expression of MAPT have been shown to be protected against β-amyloid (Aβ)-induced synaptotoxicity, as well as against stress-induced and seizure-induced neuronal damage, and against learning and memory deficits resulting from traumatic brain injury. Moreover, reducing transgenic tau expression, even after tau has accumulated in mouse models of tauopathy, reverses the pathological effects of tau. These findings support the idea that the reduction of tau protein could be used as a therapeutic approach in AD or other tauopathies.
Translation of the neuroprotective effect of tau repression into a therapeutic approach for neurodegenerative diseases requires a treatment that reduces endogenous tau in the adult brain. We created a way to generate efficient, specific, and long-lasting down-regulation of the expression of endogenous tau by using a single viral administration: AAV encoding engineered zinc finger protein (ZFP) arrays that precisely target a short region of the genomic mouse MAPT sequence and down-regulate MAPT gene expression.
Using different AAV serotypes, we were able to reduce tau locally in the hippocampus - a brain region that is specifically affected by tau pathology in neurodegenerative diseases - through intracranial injections of AAV9 or brain-wide through intravenous delivery of blood-brain barrier-crossing AAV-PHP.B. In both cases, a single AAV administration was sufficient to repress tau mRNA and all isoforms of the protein by 50 to 80% in the brain and for as long as we carried out the study - nearly 1 year - following the treatment.
Furthermore, we performed proof-of-principle experiments for the use of tau-targeted ZFP-TFs to treat neurodegeneration in a mouse model in vivo: The repression of endogenous tau appeared to protect neurons from toxicity in mice with AD-like Aβ pathology (APP/PS1 mice). Tau repression by ZFP-TFs reduced amyloid plaque-associated neuritic dystrophies, which are a tau-dependent pathological hallmark in these mice.