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We previously demonstrated that the neurotrophin brain\u2010derived neurotrophic factor (BDNF) exerts antioxidant and anti\u2010inflammatory effects in cultured rat astrocytes. Given the critical role of astrocytes in maintaining redox homeostasis, we investigated oxidative stress in cortical and striatal astrocytes from the zQ175 knock\u2010in mouse model of HD and examined the role of BDNF in modulating oxidative stress in HD astrocytes. We found early and region\u2010specific oxidative stress in mitochondrial extracts from the striatum of zQ175 HD mice and cultured striatal HD astrocytes, evidenced by elevated levels of reactive oxygen species, while cortical mitochondria remained unaffected. This was associated with reduced glutathione (GSH) levels and altered expression of key mitochondrial antioxidant proteins, including superoxide dismutase 2 (SOD2) and uncoupling protein 4 (UCP4), specifically in the striatum. Importantly, bioinformatic analyses of HD patient samples corroborated these findings. Treatment of primary HD striatal astrocytes with BDNF (50\u2009ng\/mL) prevented oxidative stress, while cortical astrocytes showed no significant response, highlighting a region\u2010specific protective effect. Astrocyte conditioned media (ACM) from BDNF\u2010treated wild\u2010type or HD astrocytes promoted the survival of mHTT expressing STHdh\u2010Q111 striatal neuronal cells. However, depletion of mitochondria from ACM abolished this protective effect, indicating that mitochondria can be transferred from astrocytes to neurons. We confirmed the presence of mitochondria in ACM and demonstrated their uptake by STHdh\u2010Q111 cells. Mitochondria isolated from untreated HD astrocytes were internalized but failed to enhance neuronal viability. In contrast, mitochondria derived from BDNF\u2010treated HD astrocytes significantly restored neuronal survival. Together, these findings reveal a selective vulnerability of the HD striatum to oxidative stress and underscore the therapeutic potential of BDNF in restoring astrocyte function, enhancing mitochondrial support, and mitigating neurodegeneration in Huntington's disease.<\/jats:p>\n                  <jats:p>\n                    <jats:boxed-text content-type=\"graphic\" position=\"anchor\">\n                      <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc70276-gra-0001-m.png\">\n                        <jats:alt-text>image<\/jats:alt-text>\n                      <\/jats:graphic>\n                    <\/jats:boxed-text>\n                  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