Abnormal accumulation of the tau protein in cerebral neurons contributes to the pathogenesis of more than a dozen neurodegenerative diseases, most notably Alzheimer?s disease (AD). Individuals afflicted with these tauopathies have little therapeutic recourse. Preventing tau deposition or promoting its clearance is one intuitively appealing treatment approach. Here we propose to explore one such strategy. The proposal is in response to an FOA described in NOT-AG-20-008 and serves as a supplement to our parent project - Spinal muscular atrophy (SMA): Mechanisms and treatment strategies (R01 NS1042108). SMA, a common monogenic motor neuron disorder caused by low SMN protein, constitutes an excellent paradigm to study general mechanisms underlying selective neuronal loss in common human diseases. While pursuing the objectives of our parent project, we discovered a potent genetic modulator of the SMA phenotype. Transgenic expression of the modulator arrests motor neuron loss and turns a severe SMA phenotype into a decidedly mild one. Interestingly, the modulator, a variant of a synaptic chaperone known to play a role in neuronal proteostasis is also reported to govern tau stability and function. In cultured cells, inhibiting the chaperone was found to aid in the removal of tau by the proteasome. This effect on tau dynamics has, however, not been investigated in the intact organism. Here we wish to address this critically important and clinically relevant gap in our understanding of tau biology. To do so we will employ the rTg(tauP301L)4510 rodent model. We will introduce onto this mutant background the chaperone variant and determine if and how disease in this model of AD is altered when the chaperone is constitutively expressed. We will also determine the course of disease in the model when the variant chaperone is delivered ? by means of a viral vector ? following symptom onset. We hypothesize that the variant form of the chaperone promotes tau triage for degradation in the proteasome. Accordingly, we expect it to mitigate the disease phenotype of the rTg4510 mice. A modification of disease in the mutants will be of dual consequence. First, it will constitute important proof-of-concept of one potentially useful means of treating AD and other tau-related dementias. Moreover, it will reveal a novel therapeutic target for combating the devastating effects of this class of neurodegenerative disease.
Abnormal accumulation of tau in brain neurons is strongly associated with age-related dementias such as Alzheimer?s disease (AD). Preventing such accumulation could constitute a treatment for AD. In this proposal we will test the ability of a protein known to regulate tau accumulation in cultured cells to also suppress tau pathology in a mouse model of AD. Showing that this is possible could suggest a path forward for the treatment of human patients with AD.
