During the course of our research, we have found our attention inexorably drawn to a well-known and very widely studied gene that is mutated in more than 55 percent of all cancers, p53. P53 functions as a sequence-specific transcription factor, which upon activation by a variety of cellular stresses, activates downstream target genes, through which it regulates the cell cycle, DNA repair, and apoptosis. Our own data and that of others, along with recent advances in the p53 field, lead us to believe that the p53 family is a central player in AD pathology.

We have shown that p73, a homologue of p53 preferentially expressed in brain, is able to phosphorylate tau (Hooper et al., 2006), as does p53 itself (Hooper et al., 2007). In fact, the third member of the family, p63, is also capable of doing this (our own unpublished data). This phenomenon only applies to those forms of the p53 family that contain the transactivation domain (TA). The forms that lack this domain, the ΔN forms, do not exert this effect.

Tau phosphorylation is reduced in the p53 KO mouse (Ferreira and...  Read more

During the course of our research, we have found our attention inexorably drawn to a well-known and very widely studied gene that is mutated in more than 55 percent of all cancers, p53. P53 functions as a sequence-specific transcription factor, which upon activation by a variety of cellular stresses, activates downstream target genes, through which it regulates the cell cycle, DNA repair, and apoptosis. Our own data and that of others, along with recent advances in the p53 field, lead us to believe that the p53 family is a central player in AD pathology.

We have shown that p73, a homologue of p53 preferentially expressed in brain, is able to phosphorylate tau (Hooper et al., 2006), as does p53 itself (Hooper et al., 2007). In fact, the third member of the family, p63, is also capable of doing this (our own unpublished data). This phenomenon only applies to those forms of the p53 family that contain the transactivation domain (TA). The forms that lack this domain, the ΔN forms, do not exert this effect.

Tau phosphorylation is reduced in the p53 KO mouse (Ferreira and Kosik, 1996). Now the Kaplan group have shown that in brains of old but not young p73+/- mice there are accumulations of phospho-tau-positive paired helical filaments (p-PHF-tau) reminiscent of tangles. Moreover, when crossed to the TgCRND8 mouse model of AD (a double APP mutant) the resultant mice show early and robust formation of p-PHF-tau tangle-like structures. This would appear to be at odds with our own work and the observations made in the p53 KO mouse. However, it can be explained if, with regard to tau phosphorylation, p53 is the main driver of tau phosphorylation and that in brain the ΔN forms of p73 repress this. The knocking out of one copy of p73 would reduce the expression of both TA and ΔN forms of p73, leading to increased p53 activity and increased tau phosphorylation. Indeed, the authors argue along these lines themselves. The p53 family is now clearly implicated in the hyperphosphorylation of tau tangle formation.

References:
Ferreira A, Kosik KS. Accelerated neuronal differentiation induced by p53 suppression. J Cell Sci. 1996 Jun;109 ( Pt 6):1509-16. Abstract

Hooper C, Meimaridou E, Tavassoli M, Melino G, Lovestone S, Killick R. p53 is upregulated in Alzheimer's disease and induces tau phosphorylation in HEK293a cells. Neurosci Lett. 2007 May 11;418(1):34-7. Abstract

Hooper C, Tavassoli M, Chapple JP, Uwanogho D, Goodyear R, Melino G, Lovestone S, Killick R. TAp73 isoforms antagonize Notch signalling in SH-SY5Y neuroblastomas and in primary neurones. J Neurochem. 2006 Nov;99(3):989-99. Abstract

View all comments by Richard Killick

This paper reporting the role of p73 in regulating neurodegeneration and tau phosphorylation during aging and Alzheimer disease is very exciting. It provides strong validation for the balance of the p53 family in the control of neuronal fate (survival versus apoptosis).

This work also offers strong support for p73, the p53 family member with highest expression in the PNS and CNS (Yang et al., 2000; Pozniak et al., 2000), as a key element in the survival versus apoptosis balance in neurons.

P73 is a structural and functional homolog of p53 (Irwin and Kaelin, 2001). There are many different p73 protein isoforms—resulting from C-termini alternative splicing and the use of two different promoters—which fall into two classes: 1) full-length, or TAp73 proteins that have a N-terminal domain (TA) participate in DNA damage-induced cell-cycle arrest or apoptosis (Agami et al., 1999;   Read more

This paper reporting the role of p73 in regulating neurodegeneration and tau phosphorylation during aging and Alzheimer disease is very exciting. It provides strong validation for the balance of the p53 family in the control of neuronal fate (survival versus apoptosis).

This work also offers strong support for p73, the p53 family member with highest expression in the PNS and CNS (Yang et al., 2000; Pozniak et al., 2000), as a key element in the survival versus apoptosis balance in neurons.

P73 is a structural and functional homolog of p53 (Irwin and Kaelin, 2001). There are many different p73 protein isoforms—resulting from C-termini alternative splicing and the use of two different promoters—which fall into two classes: 1) full-length, or TAp73 proteins that have a N-terminal domain (TA) participate in DNA damage-induced cell-cycle arrest or apoptosis (Agami et al., 1999; Gong et al., 1999; Yuan et al., 1999; Melino et al., 2004), and 2) ΔNp73, or short-form proteins, which lack the TA domain. The ΔNp73 proteins cannot induce apoptosis, but instead appear to block the function of full-length forms showing anti-apoptotic properties.

In PNS and CNS, the principally expressed p73 isoforms are DNp73, which prevent neuronal apoptosis during development (Walsh et al., 2004). Overexpression of ΔNp73 inhibits sympathetic neuronal apoptosis caused by NGF withdrawal and apoptosis of cortical neurons induced by camptothecin (Pozniak et al., 2000; Pozniak et al., 2002; Walsh et al., 2004).

The results of this paper emphasize and reinforce the role of p73 as a protective gene in neurons, since a decrease in the expression of the p73 that is normally expressed in healthy neurons (the truncated isoforms) results in a diminished ability of the cells to face damage or insults. Moreover, this work brings the protective role of DNp73 from a developmental neuronal death context to the neurodegeneration and pathology context, because perturbations of its function may accelerate neuronal aging and/or predispose to neurodegenerative disorders.

However, the role of p73 in neurodegeneration may not be limited to a protective role (performed by DNp73). We have described that p73 increases during neuronal damage induced by β amyloid (Alvarez et al., 2004), and that the TAp73 proapoptotic isoform and its apoptotic function are activated in neurodegeneration models (Cancino et al., 2008; Alvarez et al., 2008).

TAp73 isoforms are regularly removed in healthy cells through the ubiquitin-proteasome system; however, in response to cell damage, the activated c-Abl kinase regulates p73 protein levels by phosphorylating and stabilizing it (Tsai and Yuan, 2003). In non-neuronal systems c-Abl is the activator of p73 and controls growth arrest and apoptotic response to genotoxic stress (Wang and Ki, 2001).

We have found that the c-Abl/p73 pathway participates in AD neurodegeneration. The c-Abl/p73 system is activated in cultured neuronal cells exposed to β amyloid and in two Alzheimer disease (AD) in vivo models—rats exposed to β amyloid hippocampal injections and transgenic APPsewPSEN1dE9 mice (Cancino et al., 2008). In these models the intraperitoneal administration of imatinib mesylate (STI571), a c-Abl inhibitor, reduced the behavioral deficit induced by β amyloid as well as apoptosis and tau phosphorylation (Cancino et al., 2008).

In agreement with a role for TAp73 in AD, levels of p73 have been reported to be increased in the nuclei of AD pyramidal neurons, and p73 is present in dystrophic neurites with cytoskeletal pathology (Wilson et al., 2004). In this context, some p73 gene polymorphisms—probably associated with the relative expression of p73 isoforms—have been linked to AD (Li et al., 2004). In addition, it has been recently shown that p73 is activated in striatal neurons of Huntington disease patients (Hoshino et al., 2006) and in motor neurons of an ALS mouse model (Martin et al., 2007). Therefore, it is possible that the activation of the c-Abl/p73 module is a common pathological mechanism participating in a number of neurodegenerative diseases.

We have also explored the relationship between Niemann-Pick type C (NPC) disease neurodegeneration and activation of the c-Abl/p73 apoptotic system (Alvarez et al., 2008). We found that both c-Abl and p73 proteins are expressed in the cerebellum, the region most affected in NPC brains. In Purkinje cells of NPC mice, expression of the proapoptotic, phosphorylated p73 colocalized with c-Abl and active caspase 3, and p73-proapoptotic target gene levels were increased in NPC cerebellum. Strikingly, inhibition of c-Abl kinase with imatinib mesylate reduced weight loss, neurological symptoms, and cerebellar apoptosis, increasing Purkinje cell numbers and survival of NPC mice.

Because TAp73 isoforms are regularly removed in healthy cells through the ubiquitin-proteosome system, it might be difficult to detect TAp73 in total brain. However, there are some neuronal populations that express TAp73, including the hippocampus (Cabrera-Socorro et al., 2006). Damage signals stabilize TAp73 and induce an increase of its levels; therefore, damage can change the balance between the anti-apoptotic and proapoptotic p53 family members.

Moreover, in sympathetic neurons, p63 (another p53 homolog) is essential for developmental neuronal death (Jacobs et al., 2005).

The Wetzel et al. paper also shows that JNK signaling is a key element in the p53 family member’s functions, and the balance between survival and death in neurons. And more interesting, JNK signaling regulates P-tau levels—a central issue in neurodegeneration.

This wonderful paper highlights the central role of the p53 family in the nervous systems—not only in development but also in neurodegeneration—and opens new questions about the complex functions and crosstalk between these proteins. What is the protein expression profile for the different p73 isoforms in neuronal populations or brain areas? Are there other signaling pathways that control p73 function upstream in neurons?

View all comments by Alejandra Alvarez

This is an exciting paper whose results may trigger a series of follow-up studies. Several questions could be studied further. Being a transcription factor, how does p73 regulate and/or interact with APP to cause early onset of AD-like pathology? Specifically, how could this lead to P-PHF? AD is a chronic neurodegenerative disease, whereas TgCRND8+/- mice exhibit an extremely quick response and develop plaques much earlier than the Tg2576 and APP23 strains. The p73+/-/TgCRND8+/- mice start showing AD-like pathology at 1.5 or two months of age. It would be interesting to see whether p73+/- mice crossed with Tg2576 and APP23 transgenic mice would also generate early onset of AD-like pathology. For microglial activation, it seems that the glial activation may be caused by the p73 knockout. It need not necessarily be relevant to Aβ in this model, as p73+/- mice alone exhibit glial activation. Thus, p73 may have more functions to further explore. For example, does p73 affect APP processing? Does p73 affect Aβ degradation enzymes? Beside JNK, does p73 influence other kinases that may...  Read more

This is an exciting paper whose results may trigger a series of follow-up studies. Several questions could be studied further. Being a transcription factor, how does p73 regulate and/or interact with APP to cause early onset of AD-like pathology? Specifically, how could this lead to P-PHF? AD is a chronic neurodegenerative disease, whereas TgCRND8+/- mice exhibit an extremely quick response and develop plaques much earlier than the Tg2576 and APP23 strains. The p73+/-/TgCRND8+/- mice start showing AD-like pathology at 1.5 or two months of age. It would be interesting to see whether p73+/- mice crossed with Tg2576 and APP23 transgenic mice would also generate early onset of AD-like pathology. For microglial activation, it seems that the glial activation may be caused by the p73 knockout. It need not necessarily be relevant to Aβ in this model, as p73+/- mice alone exhibit glial activation. Thus, p73 may have more functions to further explore. For example, does p73 affect APP processing? Does p73 affect Aβ degradation enzymes? Beside JNK, does p73 influence other kinases that may phosphorylate tau?

The recent paper in Brain (Cancino et al., 2008) demonstrates that p73 protein mainly has two isoforms: 1) the full-length TAp73 protein whose N-terminal domain participates in cell-cycle arrest or apoptosis induced by DNA-damage and 2) Np73 short proteins lacking this domain. These cannot induce apoptosis but instead appear to block the function of full-length forms. Cancino et al. mainly focus on the full-length p73 protein. Using antibodies that recognize the TAp73 or truncated Np73 isoforms, they found that Aβ induced a significant increase in the TAp73 isoform level, whereas Np73 isoforms were moderately decreased. Wetzel et al. propose that the reported neurodegeneration phenotypes are the result of reduced levels of Np73, which is the only detectable p73 isoform in the postnatal mouse CNS. In this sense, the data in both papers fit together.

View all comments by Yong Shen