SEX- AND REGION-SPECIFIC TRKB ISOFORM IMBALANCE AND AMYLOID-BETA MODULATION IN 5XFAD MICE

Alzheimer’s disease (AD) shows sex disparities, with females exhibiting earlier affective and cognitive decline and pronounced amygdalar atrophy. The BDNF/TRKB neurotrophic pathway, essential for synaptic maintenance and neuronal survival, becomes dysregulated in AD, where reduced TRKB.FL and increased dominant-negative TRKB.T1 compromise signaling toward a synaptotoxic profile and amplifies amyloid-beta (Aβ)-associated neuronal stress. The regional and sex-specific dynamics of TRKB isoform imbalance and its interaction with Aβ pathology remain insufficiently defined. To address this, male and female 5xFAD mice were evaluated at 3, 4.5, and 6 months of age. TRKB.FL and TRKB.T1 expression, Aβ burden, and glial-inflammatory markers (GFAP, IBA1) were quantified in the amygdala, hippocampus, and prefrontal cortex (PFC). A parallel cohort received early Aβ-attenuation immunotherapy to test whether Aβ reduction modifies neurotrophic signaling, neuroinflammation, and cognition in a sex- and region-dependent manner. Behavioral assessments measured recognition memory and learning-dependent performance. Results revealed that females, but not males, display a detectable elevation in amygdalar TRKB.T1 by 3 months, preceding neuroinflammatory activation. Aβ attenuation selectively prevented the rise of TRKB.T1 only among females, reduced GFAP and IBA1 expression, and increased behavioral effect sizes, indicating a significant therapy, sex and region interaction. These data identify Aβ-driven elevation of TRKB.T1 as a reversible, sex- and region-selective pathogenic switch. The female amygdala emerges as an early vulnerability node, defining a therapeutic window in which targeted Aβ modulation may stabilize TRKB signaling, limit neuroinflammation, and modify disease trajectory.