Targeting structural plasticity to improve Alzheimer disease-related functional deficits

Synaptic and neuronal loss is a central and early feature of Alzheimer disease (AD) that is closely associated with cognitive decline. Mouse models of AD, which are critical for the development of novel therapeutics, develop Abeta or tau pathology but many of these models fail to develop substantial synaptic or neuronal loss. We investigated the therapeutic potential of targeting structural plasticity in two complementary transgenic mouse models: the 3xTg-AD model, which develops Abeta and tau pathology, and the CaM/Tet-DTA model, which harbors a genetically-inducible transgene system that causes severe synaptic and neuronal loss in AD-relevant brain regions. The use of both of these models ensures that we are investigating all of the most critical features of AD.;We created a novel, GFP-expressing variant of the CaM/Tet-DTA model that facilitates a detailed analysis of structural plasticity following lesion and treatment. Following lesion, we found a significant elevation in the density of thin spines. Although lesioned mice have substantial cognitive deficits, this lesion-induced plasticity may be evidence of a compensatory response.;Our studies highlight BDNF-TrkB signaling as a promising therapeutic target for reversing AD-related cognitive deficits. Previous work in our lab found that neural stem cell transplantation increases synaptic density and reverses cognitive deficits in 3xTg-AD mice, and our current experiments identify BDNF as a critical mediator of these benefits. Furthermore, our studies determined that BDNF likely does not drive Abeta or tau pathogenesis in 3xTg-AD mice, which suggests BDNF deficits in AD patients are likely a downstream consequence of these pathologies.;Since BDNF has various practical limitations for clinical use such as poor blood-brain penetrability and a short half-life, we investigated the impact of a novel, small molecule TrkB agonist, 7,8-dihydroxyflavone (DHF) in CaM/Tet-DTA mice. We found that chronic, systemic treatment with 7,8-DHF significantly improved hippocampus-dependent learning and memory. Furthermore, 7,8-DHF interacted synergistically with signaling for lesion-induced plasticity to further elevate the density of thin dendritic spines.;Together, our studies highlight the therapeutic potential of facilitating signaling pathways that underlie structural plasticity. Even once disease-modifying treatments are improved to the point where they are able to stop the progression of AD, treatments that target structural plasticity will be essential for restoring lost connectivity and reversing functional deficits.