Cystatin C prevents neuronal loss and behavioral deficits via the endosomal pathway in a mouse model of down syndrome

Cystatin C (CysC) plays diverse protective roles under conditions of neuronal challenge. We investigated whether CysC protects from trisomy-induced pathologies in a mouse model of Down syndrome (DS), the most common cause of developmental cognitive and behavioral impairments in humans. We have previously shown that the segmental trisomy mouse model, Ts[Rb(12.1716)]2Cje (Ts2) has DS-like neuronal and behavioral deficiencies. The current study reveals that transgene-mediated low levels of human CysC overexpression has a preventive effect on numerous neuropathologies in the brains of Ts2 mice, including reducing early and late endosome enlargement in cortical neurons and decreasing loss of basal forebrain cholinergic neurons (BFCNs). Consistent with these cellular benefits, behavioral dysfunctions were also prevented, including deficits in nesting behavior and spatial memory. We determined that the CysC-induced neuroprotective mechanism involves activation of the phosphotidylinositol kinase (PI3K)/AKT pathway. Activating this pathway leads to enhanced clearance of accumulated endosomal substrates, protecting cells from DS-mediated dysfunctions in the endosomal system and, for BFCNs, from neurodegeneration. Our findings suggest that modulation of the PI3/AKT pathway offers novel therapeutic interventions for patients with DS. •Cystatin prevents trisomy-induced pathologies in a Down syndrome mouse model.•Cystatin C neuroprotection is via activation of the PI3K/AKT signaling pathway.•PI3K/AKT stimulation leads to normal flux through the endosomal-lysosomal system.•Restoration of normal endosomal function prevents memory dysfunction.•Modulation of the PI3/AKT pathway, a novel therapy for neurodegenerative disorders.