A three-dimensional dementia model reveals spontaneous cell cycle re-entry and a senescence-associated secretory phenotype.

A hexanucleotide repeat expansion on chromosome 9 open reading frame 72 (C9orf72) is associated with familial amyotrophic lateral sclerosis (ALS) and a subpopulation of patients with sporadic ALS and frontotemporal dementia. We used inducible pluripotent stem cells from neurotypic and C9orf72+ (C9+) ALS patients to derive neuronal progenitor cells. We demonstrated that C9+ and neurotypic neuronal progenitor cells differentiate into neurons. The C9+ neurons, however, spontaneously re-expressed cyclin D1 after 12 weeks, suggesting cell cycle re-engagement. Gene profiling revealed significant increases in senescence-associated genes in C9+ neurons. Moreover, C9+ neurons expressed high levels of mRNA for CXCL8, a chemokine overexpressed by senescent cells, while media from C9+ neurons contained significant levels of CXCL8, CXCL1, IL13, IP10, CX3CL1, and reactive oxygen species, which are components of the senescence-associated secretory phenotype. Thus, re-engagement of cell cycle-associated proteins and a senescence-associated secretory phenotype could be fundamental components of neuronal dysfunction in ALS and frontotemporal dementia.

The Promise and Perils of Compound Discovery Screening with Inducible Pluripotent Cell-Derived Neurons.

Neurological diseases comprise more than a thousand ailments that adversely affect the brain and nervous system. When grouped together, these neurological conditions impact an estimated 100 million individuals in the United States and up to a billion people worldwide, making drug discovery efforts imperative. However, recent research and development efforts for these neurological diseases, including Alzheimer's disease and amyotrophic lateral sclerosis, have been exceedingly disappointing and typify the challenges associated with translating in vitro and cell-based discoveries to successful preclinical models and subsequent human clinical trials. Our viewpoint is that neuronal progenitor cells and neurons derived from inducible pluripotent stem cells afford an innovative translational bridge, with higher pathological relevancy than previous cellular models. We outline some of the opportunities and challenges associated with their evolving usage in drug discovery and development.

Aberrant Neuronal Cell Cycle Re-Entry: The Pathological Confluence of Alzheimer's Disease and Brain Insulin Resistance, and Its Relation to Cancer.

Aberrant neuronal cell cycle re-entry (CCR) is a phenomenon that precedes and may mechanistically lead to a majority of the neuronal loss observed in Alzheimer's disease (AD). Recent developments concerning the regulation of aberrant neuronal CCR in AD suggest that there are potential intracellular signaling "hotspots" in AD, cancer, and brain insulin resistance, the latter of which is characteristically associated with AD. Critically, these common signaling nodes across different human diseases may represent currently untapped therapeutic opportunities for AD. Specifically, repurposing of existing US Food and Drug Administration-approved pharmacological agents, including experimental therapeutics that target the cell cycle in cancer, may be an innovative avenue for future AD-directed drug discovery and development. In this review we discuss overlapping aspects of AD, cancer, and brain insulin resistance from the perspective of neuronal CCR, and consider strategies to exploit them for prevention or therapeutic intervention of AD.