Abstract
Cyclin-dependent kinase 5 (CDK5) regulates important neuronal functions via p35. p35 undergoes cleavage in response to neuronal activity and neurotoxic conditions to release its subunit p25. Although p25 has been implicated in various neurodegenerative diseases, the mechanisms by which p25 mediates neurodegenerative impairment have not been fully elucidated. We aimed to determine the role of p25-mediated neurodegeneration on neurogenesis in an inducible transgenic mouse line overexpressing p25 (p25 TG) in the forebrain. Adult neuronal progenitor cells (NPCs) were labeled with BrdU in vivo, which were significantly increased in numbers in the subventricular zone, the hippocampus, and the cortex of p25 TG mice. Consistently, more mitotic cells were observed in p25 TG mice than in controls, even in the cortex and the CA1, which are not neurogenic regions. BrdU-positive cells were negative for GFAP or γ-H2AX, suggesting that they are not astrocytes or dying cells. Neurospheres derived from the dentate gyrus and the cortex were significantly increased in p25 TG mice and can be differentiated into astrocytes and neurons. However, p25 TG decreased the long-term survival of proliferating NPCs and severely impaired adult neurogenesis. A Transwell co-culture system was used to assess the influence of p25-expressing primary neurons on adult NPCs. Co-culture with p25-expressing neurons downregulated Ki67 expression and upregulated cleaved caspase-3, indicating that the paracrine signaling in cell-cell communication is essential for NPC survival and proliferation. Moreover, increased CDK5 activity impairs Wnt activation. This study demonstrates that hyperactivation of p25 may temporarily enhance NPC proliferation, but impair their long-term survival.
Highlights
Cyclin-dependent kinases (CDKs) are a group of protein kinases with crucial roles in regulating the cell cycle [1]
To determine the p25-mediated cell toxicity on neurogenesis, we established a bitransgenic mouse line in which inducible green fluorescent protein (GFP)-tagged human p25 expression is controlled by the CamKII promoter (CK)-regulated tet-off system
The accumulation of p25 has been linked to neurodegenerative diseases such as Alzheimer’s disease (AD) [19], the effects of p25 in neurogenesis and differentiation are still poorly understood
Summary
Cyclin-dependent kinases (CDKs) are a group of protein kinases with crucial roles in regulating the cell cycle [1]. The Cdk5/p25 association is longer and uncontrolled, causing aberrant hyperphosphorylation of various Cdk substrates, such as amyloid precursor protein, tau, and neurofilaments, leading to neurodegenerative pathology, including Alzheimer’s disease (AD) [16,17,18,19]. Accumulation of p25 may contribute to neurotoxicity and neuronal death in AD pathology by inducing abnormal CDK5 activity and subsequently triggering inappropriate cell-cycle re-entry in mature neurons [8, 20, 21]. P25 accumulation causes neurodegeneration in pathological conditions, but the precise role of p25induced neurotoxity in neuronal development and differentiation has not yet been fully clarified [26] A number of reports have described a correlation between neuronal activity and Aβ production [22, 23], and p25 overexpression increases Aβ levels in vivo via a mechanism involving BACE1 [24, 25]. p25 accumulation causes neurodegeneration in pathological conditions, but the precise role of p25induced neurotoxity in neuronal development and differentiation has not yet been fully clarified [26]
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