The neuroprotective effects of cyclin-dependent kinase-5 inhibition in mice with Niemann-Pick disease type C.

In order to investigate the neuroprotective effects of cyclin-dependent kinase-5 (cdk-5) inhibition in mice with Niemann-Pick disease type C (NPC) (npc(-/-)), recombinant adeno-associated virus (rAAV) carrying the small interfering RNA (siRNA) specific for cdk-5 gene was injected into 3-day-old npc(-/-) mice intracerebroventricularly. The rAAV-GFP-injected age-matched npc(-/-) mice and non-surgery age-matched npc(-/-) mice were employed as controls (n=6-10/group). From the 4th to 8th week after the treatment, mice were weighed, and evaluated for limb motor activity by using the coat hanger test once a week. Eight-week-old npc(-/-) mice were sacrificed by decapitation, and brains were quickly dissected and halved sagittally. Immunohistochemistry, Western blotting, and HE staining were used to evaluate the neuropathology in npc(-/-) mice. The results showed that rAAV-cdk-5-siRNA-GFP significantly reduced the number of axonal spheroids, delayed the death of Purkinje neurons, ameliorated motor defects in npc(-/-) mice, and significantly attenuated the hyperphosphorylation of tau proteins. These data suggested that inhibition of cdk-5 activity has neuroprotective effect on neurons in NPC mice.