Within the overarching theme of 'Proteinopathies of the Aging Central Nervous System,' Project 5 hasfocused on Alzheimer's disease (AD). The insights we gained during the preceding funding period and theever increasing threat AD poses to public health have motivated us to maintain this focus in the currentproposal. We will also continue to utilize transgenic mice with neuronal expression of human amyloidprecursor proteins (hAPP) and amyloid-p (A(3) peptides, because there is substantial evidence formechanistically informative overlap between these models and the human condition. In our originalapplication, we promised to shed light on the processes by which Ap elicits neuronal deficits. We found thatneurons in the dentate gyrus and entorhinal cortex brain regions affected early and severely by AD areparticularly vulnerable to the A|3-induced depletion of proteins that are critical for learning and memory.Several molecules were identified that may mediate this process. We also identified strategies to prevent A|3-induced neuronal deficits in hAPP mice. For example, reduction of the tau protein effectively prevented A(3-dependent memory deficits and molecular neuronal alterations. Although the mechanism underlying thisstriking rescue remains to be fully elucidated, we already know that it does not depend on changes in A(3levels or deposition. Rather, tau reduction appears to prevent aberrant increases in neuronal networkexcitability. Our new proposal builds on the most promising findings we obtained during the precedingfunding period.
In Aim 1, we will examine whether A|3 affects vulnerable neurons directly or indirectly throughchanges in other regions from which these neurons receive excitatory inputs.
In Aim 2, we will determine ifthe modulation of excitotoxicity-related neuronal or glial molecules can block Ap-induced neuronaloverexcitation, eliminate aberrant network activities, and ameliorate behavioral abnormalities in hAPP mice.
In Aim 3, we will assess whether tau reduction can prevent neuronal deficits also in mouse models ofParkinson's disease and Huntington's disease. Confirmation of these untested hypotheses should helpelucidate the mechanisms that underlie A|3-dependent cognitive deficits and pave the way for thedevelopment of better treatments for AD and other neurological disorders. The proposed studies involvecollaborative interactions with all other project leaders and depend on support from all four cores. Themechanistic and therapeutic insights we will gain in this project should help answer some of the keyquestions pursued in the other projects and, thus, will benefit the program as a whole.
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