Cyclin-dependent kinase 5 (Cdk5) is required for proper development of the mammalian central nervous system. To be activated, Cdk5 has to associate with its regulatory subunit, p35. We have found that p25, a truncated form of p35, accumulates in neurons in the brains of patients with Alzheimer's disease. This accumulation correlates with an increase in Cdk5 kinase activity. Unlike p35, p25 is not readily degraded, and binding of p25 to Cdk5 constitutively activates Cdk5, changes its cellular location and alters its substrate specificity. In vivo the p25/Cdk5 complex hyperphosphorylates tau, which reduces tau's ability to associate with microtubules. Moreover, expression of the p25/Cdk5 complex in cultured primary neurons induces cytoskeletal disruption, morphological degeneration and apoptosis. These findings indicate that cleavage of p35, followed by accumulation of p25, may be involved in the pathogenesis of cytoskeletal abnormalities and neuronal death in neurodegenerative diseases.

SUMMARY How adult tissue stem and niche cells respond to the nutritional state of an organism is not well understood. Here, we find that Paneth cells, a key constituent of the mammalian intestinal stem cell (ISC) niche, augment stem cell function in response to calorie restriction (CR). CR acts by reducing mTOR complex 1 (mTORC1) signaling in Paneth cells, and the ISC-enhancing effects of CR can be mimicked by rapamycin. Calorie intake regulates mTORC1 in Paneth cells, but not ISCs, and forced mTORC1 activation in Paneth cells during CR abolishes their effects on ISCs. Finally, increased expression in Paneth cells of bone stromal antigen 1 (Bst-1), an ectoenzyme that produces the paracrine factor cyclic ADP ribose (cADPR), mediates the effects of CR and rapamycin on ISC function. Our findings establish that mTORC1 non-cell autonomously regulates stem cell self-renewal, and highlight a significant role of the mammalian intestinal niche in coupling stem cell function to organismal physiology.