Aging entails distinct requirements for Rb at maintaining adult neurogenesis

Rb deficiency, neuronal survival and neurodegeneration: In search of the perfect mouse model

“…This is critical, as it opposes the mechanism by which Rb inactivation likely causes AD-like neurodegenerative phenotypes along the same pathway: in rat primary cortical neurons, Rb expression is downregulated by the overexpression of miR-26b (seen in AD patients), leading to CCE and an increased kinase activity of Cdk5 by p25/p35 which then hyperphosphorylates Tau ( Absalon et al, 2013 ). As such, the ‘anti-neurodegenerative’ role of Tamoxifen might partially explain why, 210- and 480-days following Rb iKO in adult-born neurons of the aged OB, we could not detect a significant tau hyperphosphorylation signal in these Rb-deficient neurons ( Omais et al, 2022 ) ( Fig. 3 ).…”

“…Since this model triggered Rb deletion before differentiation, it was also essential to distinguish CCE in postmitotic neurons from a delayed cell cycle exit scenario upon differentiation. This was indeed established by coupling the Rb iKO model with BrdU birthdating, which labels a subset of postmitotic adult-born OB neurons ( Omais et al, 2022 ).…”

“…at P90, Rb inactivation in the adult subventricular zone (aSVZ) leads to a more controlled boost in progenitors’ proliferation without affecting subsequent migration and differentiation of committed neuroblasts into mature olfactory bulb interneurons ( Naser et al, 2016 ). Of interest, we recently showed that in the aSVZ of mid-aged (P360) and old-aged (P600) mice, Rb becomes almost completely dispensable in regulating division of neural stem and progenitor cells; it is, however, once again required for the early maturation of migrating neuroblasts and their subsequent survival ( Omais et al, 2022 ). Therefore, with age and in the absence of Rb, the resulting neuronal progeny is least compromised in young adult mice in contrast to embryonic and aged mice ( Fig.…”

“…Furthermore, Chk1 pathway suppression can possibly be what distinguishes Rb-TKO effects in cortical compared with retinal lineages ( Oshikawa et al, 2017 ). Second, in Rb-deficient adult-born OB neurons, immunostaining for endogenous cell cycle markers showed an increase in expression of PCNA (marker of interphase and mitosis) and Ki67 (S-G2-M) but not pH3 (G2-M) ( Omais et al, 2022 ). Since this model triggered Rb deletion before differentiation, it was also essential to distinguish CCE in postmitotic neurons from a delayed cell cycle exit scenario upon differentiation.…”

“…Here again, the limitations of Rb KO models are worth highlighting. For instance, Tamoxifen is used to induce Cre recombinase activation in Rb iKO systems ( Naser et al, 2016 ; Vandenbosch et al, 2016 ; Andrusiak et al, 2012 ; Omais et al, 2019 , 2022 ). However, out of 1760 candidate compounds, Tamoxifen was the only drug identified with sufficient affinity to Cdk5 as to disrupt its interaction with p25 and inhibit downstream tau phosphorylation – a defining signature of AD pathophysiology ( Corbel et al, 2015 ).…”