Table 1.

Cell cycle related molecules and events in Alzheimer’s disease (AD).

Molecules/insults	Description
Expression of cell cycle related events or proteins in AD
DNA replication	Fully or partially replicated separate genetic loci on some chromosomes identified by fluorescent in situ hybridization (Yang et al., 2001).
PCNA	Increased expression in the hippocampus and other regions in AD brains (Busser et al., 1998; Yang et al., 2003).
Cyclin B	Increased expression in certain regions in AD. Neurons with high expression of cyclin B has phosphorylated Tau, but not necessarily the tangle-like Tau (Nagy et al., 1997; Smith et al., 1999; Yang et al., 2003).
Cyclin D	Increased expression in the hippocampus and other regions in AD brains (Busser et al., 1998; Yang et al., 2003).
Cyclin E	It is also expressed more in AD brains (Nagy et al., 1997; Smith et al., 1999).
CDK4	Increased expression in AD brains (McShea et al., 1997).
P16 (CDKN2A)	Increased expression in AD brains (McShea et al., 1997).
CARB	Associated with p21 and cyclin B, involved in cell cycle; colocalizes with the tangle and granulovacuolar degeneration in AD brain neurons (Zhu et al., 2004).
c-myc and ras	Drives DNA replication and expression of cyclin B in cultured primary cortical neurons, also induces phosphorylation and conformational change of Tau (McShea et al., 2007).
p38 MAPK	Diffusively distributed in the cytoplasm in the controls, while completely overlapped with Tau tangle in AD brains in the hippocampus and cortex (Zhu et al., 2000).
RGCC	Increases in MCI and AD; and correlates with the cognitive deficit (Counts and Mufson, 2017).
BRCA1	Colocalization with the neurofibrillary tangles (Evans et al., 2007).
Mcm2	Involved in DNA replication and becomes phosphorylated by CDKs and Cdc7 during DNA synthesis (Bonda et al., 2009).
Linkage between the cell cycle and the Alzheimer proteins
APP	Phosphorylated at Thr668 in AD; phosphorylation of this site occurs during cell cycle by cdc2 kinase; the APP-binding protein (APP-BP1) is also able to trigger cell cycle progression through NEDD8 pathway (Suzuki et al., 1994; Chen et al., 2000).
Aβ	Aβ oligomers induces CCE in cultured primary neurons via Tau (Seward et al., 2013); neuronal CCE prior to Aβ deposition occurs in the APP transgenic rat brains (Varvel et al., 2008).
Tau	It can induce cell cycle related proteins and DNA synthesis in transgenic mice that overexpress human Tau (Andorfer et al., 2005; Hradek et al., 2015).
Presenilin	Overexpression arrests the cell cycle in the G1 Phase; the AD mutant promotes cell cycle arrest; presenilin deficiency in mice delays the cell cycle (Janicki and Monteiro, 1999; Janicki et al., 2000; Yuasa et al., 2002).
Cell cycle triggering or regulatory molecules and events
TNF-α	Microglial-derived TNFα induces neuronal CCE via the JNK signaling; microglia extracted from the APP transgenic mice (R1.40) drives neuronal CCEs in the host mouse brain and this can be blocked by Tnfα knockout (Bhaskar et al., 2014).
Oxidative stress	Induce CCE via DNA damage or other mechanisms (Klein and Ackerman, 2003; Lin and Beal, 2006; Silva et al., 2014).
AGEs	Indicator of oxidative stress; increased level in AD brain; colocalizes with neurons expressing cyclin D and DNA replications signs (Kuhla et al., 2015).
DNA Damage	It induces cell cycle reentry in cultured primary postmitotic neurons (Kruman et al., 2004).
Cerebral ischemia	Transient Cerebral Ischemia induces expression of mitotic proteins and tau phosphorylation in adult female rat cortex (Wen et al., 2004). Mild Cerebral Ischemia Induces Loss of CDKN2A and activation of CCE to neuronal death (Katchanov et al., 2001).
Hypoxia-Ischemia	Induces increased expression of Ki67, reduced p16INK4 and p27Kip1, upregulated CDK2 activity, and phosphorylation of Rb (Kuan et al., 2004).
Excitotoxicity	Kainic-acid treatment in vivo induces erroneous CCR in cultured primary postmitotic neurons through the Notch signaling (Marathe et al., 2015).
MiR-26b	Increased expression in AD brains as early as at Braak III; triggers DNA replication and CCE, tau phosphorylation in cultured neurons (Absalon et al., 2013).