**Author details**

In addition, also animal models developed to understand a specific pathway even in absence

In contrast, the model offered by knocking out the Pin1 gene in our Pin1KO model may recapitu‐ late some of the features characteristic of both tau and Abeta pathology in sporadic AD, and therefore could serve as a valid tool to investigate the pathways that can be targeted to prevent or halt the disease progression. In fact, Pin1KO mice 1) develop age-dependent Abeta pathology associated with early neuronal deficit that leads to neurodegeneration (elevated Abeta levels associated with increased intracellular deposition) [41], 2) are characterized by age-dependent tau hyperphosphorylation, stabilization and PHF formation [42], and 3) show age-dependent neurodegeneration in selected areas [42]. Because genetic and proteomic findings link de‐ creasedPin1levelsand/oractivitytoAD[56,61],wecouldspeculatethatthePin1KOanimalmodel be very close to recapitulating the features that characterize AD in humans, and therefore may

We have here reviewed studies showing how Pin1 is an essential regulator of APP, tau and GSK3beta conformations, maintaining their physiological functions, and how loss of Pin1 in AD contributes to the accumulation of toxic conformations that turn the proteins' function pathologic. Moreover, the data here discussed present Pin1 as a link between both Abeta and tau pathology that could be exploited to tackle both pathologies in AD, even at early stages. The emerging new concept is that protein conformation might be a key regulatory element in toxic pathways in AD, and that Pin1 regulation of protein conformations might be a promising

The debate about Abeta and tau pathology, which occurs first, which causes the other, is still unsolved, and clarifying it would help identify the correct therapeutic target to successfully prevent AD progression. Although studies in animal models in vivo showed that Abeta pathology occurs first and may be causative of tau pathology [222, 223], they were performed in animal models genetically modified to develop both tau and Abeta pathologies, and therefore may not be representative of the molecular mechanisms underlying sporadic forms of AD. In fact, it is still unclear which pathology occurs first in human AD, and only fine diagnostic tools able to identify early modification on both APP and tau that may render the

As appropriate early diagnostic tools are still missing, the evidences here presented highlight Pin1 as an ideal therapeutic target to block the toxicity of both APP and tau in AD. In fact, the data here discussed show that equilibrium between cis and trans conformation of APP and tau is crucial to maintain their physiological function, and that this is disrupted either by hyperphosphorylation at S/T-P or by lower Pin1 levels or both in AD. In addition, we show here evidences that, in tau, alteration in the equilibrium between cis and trans conformation is an event that precedes massive cognitive decline, since the cis form of phosphorylated tau accumulates in MCI patients [129]. These results directly link conformational changes to

of plaques [118], show limitations in the interpretation of the results.

serve as a valid model to study the molecular pathways involved in AD.

**7. Conclusion**

126 Understanding Alzheimer's Disease

avenue to fight AD.

proteins toxic would be of help.

Lucia Pastorino, Asami Kondo, Xiao Zhen Zhou and Kun Ping Lu

\*Address all correspondence to: lpastori@bidmc.harvard.edu

\*Address all correspondence to: klu@bidmc.harvard.edu

Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, USA
