Cancer and Alzheimer's disease inverse relationship: an age-associated diverging derailment of shared pathways.

ABSTRACT

Several epidemiological studies show an inverse association between cancer and Alzheimer's disease (AD). It is debated whether this association is the consequence of biological mechanisms shared by both these conditions or may be related to the pharmacological treatments carried out on the patients. The latter hypothesis, however, is not sustained by the available evidence. Hence, the focus of this review is to analyze common biological mechanisms for both cancer and AD and to build up a biological theory useful to explain the inverse correlation between AD and cancer. The review proposes a hypothesis, according to which several molecular players, prominently PIN1 and p53, have been investigated and considered involved in complex molecular interactions putatively associated with the inverse correlation. On the other hand, p53 involvement in both diseases seems to be a consequence of the aberrant activation of other proteins. Instead, PIN1 may be identified as a novel key regulator at the crossroad between cancer and AD. PIN1 is a peptidyl-prolyl cis-trans isomerase that catalyzes the cis-trans isomerization, thus regulating the conformation of different protein substrates after phosphorylation and modulating protein function. In particular, trans-conformations of Amyloid Precursor Protein (APP) and tau are functional and "healthy", while cis-conformations, triggered after phosphorylation, are pathogenic. As an example, PIN1 accelerates APP cis-to-trans isomerization thus favoring the non-amyloidogenic pathway, while, in the absence of PIN1, APP is processed through the amyloidogenic pathway, thus predisposing to neurodegeneration. Furthermore, a link between PIN1 and tau regulation has been found, since when PIN1 function is inhibited, tau is hyperphosphorylated. Data from brain specimens of subjects affected by mild cognitive impairment and AD have revealed a very low PIN1 expression. Moreover, polymorphisms in PIN1 promoter correlated with an increased PIN1 expression are associated with a delay of sporadic AD age of onset, while a polymorphism related to a reduced PIN1 expression is associated with a decreased risk of multiple cancers. In the case of dementias, in particular of Alzheimer's disease, new biological markers and targets based on the discussed players can be developed based on a theoretical approach relying on different grounds compared to the past. An unbiased expansion of the rationale and of the targets may help to achieve in the field of neurodegenerative dementias similar advances to those attained in the case of cancer treatment.