Drosophila CP subunits play a critical role in the organization and dynamics of lamellipodia and filopodia in non-neuronal cells. One of the mammalian b-subunit isoforms, Capzb2, is predominantly expressed in the brain. We have demonstrated that Capzb2 not only caps F-actin barbed end but also binds bIII-tubulin directly, affecting the rate and the extent of microtubule polymerization in the presence of tau. Moreover, Capzb2 – bIII-tubulin interaction is indispensable for normal growth cone morphology and neurite length. The interaction between CapZ and b-tubulin was uncovered in a mass spectrometry screen for altered protein-protein interactions in response to spatial learning. CapZ localization in the hippocampal dendritic spines has been recently shown to undergo activity-dependent, synapse-specific regulation in a rat model of dementia. BDNF is necessary for normal spatial learning and reduced BDNF and TrkB mRNA levels correlate with impaired memory performance in senescent rats. Further, lifestyle modifications that are thought to reduce the risk of developing clinical AD, such as intake of docosahexaenoic acid and increased exercise, appear to interact with BDNFrelated synaptic plasticity. Actin cytoskeleton is a wellestablished target for BDNF/TrkB signaling that affects not only memory formation and retention but also neuronal regeneration. BDNF is required for normal F-actin distribution in growth cones and for axonal protrusion during regeneration in retinal ganglion cells. As hyperphosphorylated tau gives rise to neurofibrillary tangles in AD, dystrophic neurites, marked by reduced length and poor branching, become apparent. In parallel, perisomatic proliferation of dendrites and sprouting of distal dystrophic neurites take place. The presence of growth cone-like structures on distal ends of dystrophic neurites suggests that regenerative response R428 accompanies degenerative cytoskeletal changes in AD. These morphological changes in neurons during AD progression indicate major cytoskeletal reorganization raising the possibility that microtubules and microfilaments may represent a target for pathobiological mechanisms underlying AD. Here we report a significant increase in Capzb2 protein and mRNA levels in hippocampal CA1 pyramidal neurons at mid-stage non-familial AD. The up-regulation of Capzb2 at this stage is accompanied by an increase in mRNA levels of BDNF primary receptor, TrkB. BDNF/TrkB signaling modulates cell morphology and neurite length. Our data suggest that Capzb2, a recently established link in microfilament microtubule assembly, together with BDNF/TrkB signaling, may play a role in cytoskeletal reorganization and possibly regenerative changes at specific stages of AD progression. We previously demonstrated that RNAi-mediated silencing of Capzb2 in cultured hippocampal neurons resulted in short, dystrophic neurites reminiscent of the cytoskeletal changes associated with neurodegeneration in AD. Cytoskeletal abnormalities that included dystrophic neurites, decreased dendritic areas.