Friday, November 22, 2024
11/22/2024
PROJECT SUMMARY/ABSTRACT Pathogenic tau in Alzheimer’s disease and related dementias inhibits the plasticity of neuronal connections underlying progressive memory loss. What remains undetermined, however, are the complex and multifactorial molecular events that disrupt synaptic plasticity in neurons with pathogenic tau. This is major gap in our knowledge of the molecular and physiological processes underlying memory loss in Alzheimer’s disease and related dementias. There is a critical need to uncover how plasticity is dysregulated by pathogenic tau to lay the groundwork for new strategies to target plasticity for therapeutic intervention in these diseases. Long-term potentiation (LTP) is a type of plasticity that involves the persistent strengthening of specific connections between neurons in response to increased activity. There is a strong link between memory impairments and obstructed LTP at synapses in transgenic mouse models of Alzheimer’s disease and related dementias, suggesting that the inability of synapses to express LTP is a key factor leading to memory decline. Our preliminary studies suggest that pathogenic tau blocks the activity-dependent de novo protein synthesis in dendrites that is required for LTP expression. Moreover, we found that pathogenic tau downregulates a translation initiation factor that controls activity-dependent mRNA translation during plasticity. The central hypothesis of this proposal is that pathogenic tau blocks the initiation of local protein translation in dendrites and thereby disrupts the dynamics of postsynaptic proteins that establish LTP and the encoding of new memories. To delineate the mechanism by which pathogenic tau inhibits LTP expression, we propose to use both human induced pluripotent stem cell (iPSC)-derived cultured neurons with familial tau mutations, V337M and R406W, that cause dementia and the PS19 tauopathy mouse model. We will establish the effect of pathogenic tau on the active translation of mRNAs into newly synthesized proteins during LTP expression. We will use a combination of methods to monitor the effect of tau on the rate of protein synthesis and on the subset of mRNAs that are actively translated during LTP. We will next determine the impact of pathogenic tau on a critical step in the initiation of protein translation and the extent to which restoring activity-dependent translation initiation can ameliorate LTP and memory impairments in PS19 mice assessed by electrophysiological recordings and behavioral tests of learning and memory. Finally, we will use an unbiased and innovative APEX proteomics approach to establish the impact of pathogenic tau on the dynamic changes in the postsynaptic protein composition during LTP expression that involve both de novo protein synthesis and the reorganization of protein composition to enhance synaptic strength. From these studies, we expect to elucidate the effect of pathogenic tau on dendritic protein synthesis and the regulation of postsynaptic protein dynamics that underlie the complex and multifactorial causes of memory loss in Alzheimer’s disease and related dementias.
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