Our understanding of Alzheimer’s disease (AD) pathogenesis has developed with several hypotheses over the last 40 years, including the Amyloid and Tau hypotheses. More recently, the p53 protein, well-known as a genome guardian, has gained attention for its potential role in the early evolution of AD. This is due to the central involvement of p53’s in the control of oxidative stress and potential involvement in the Amyloid and Tau pathways. p53 is commonly regulated by post-translational modifications (PTMs), which affect its conformation, increasing its capacity to adopt multiple structural and functional states, including those that can affect brain processes, thus contributing to AD development. The following review will explore the impact of p53 PTMs on its function and consequential involvement in AD pathogenesis. The greater understanding of the role of p53 in the pathogenesis of AD could result in more targeted therapies benefiting the many patients of this debilitating disease.

Ongoing research seeks to identify blood-based biomarkers able to predict onset and progression of Alzheimer’s disease (AD). The unfolded conformatio

Background: Research continues to search for blood-based biomarkers sensitive to Alzheimer’s disease (AD) pathology during the initial stages when symptoms of cognitive decline are not yet apparent. A blood-based biomarker candidate is metalloprotein p53, the conformation of which was previously found to be altered in peripheral cells from individuals with mild cognitive impairment (MCI) and AD, presenting as an unfolded p53 (U-p53) conformational variant. Methods: Plasma samples from the well-characterized Australian Imaging, Biomarkers, and Lifestyle (AIBL) cohort were used to identify the clinically relevant AZ 284® peptide, specifically present in samples from individuals with symptomatic AD. The AZ 284® peptide, which is a marker of the U-p53 conformational variant (U-p53AZ), was identified by immunoprecipitation (IP) with a novel U-p53 conformational variant-specific antibody followed by liquid chromatography (LC) tandem mass spectrometry (MS/MS) and protein sequencing. Using IP-LC surface-activated chemical ionization (SACI) MS/MS analysis, the prognostic and diagnostic performance of U-p53AZ were examined in the longitudinal AIBL cohort, including 252 plasma samples derived from 214 elderly individuals. For the prognostic analyses, U-p53AZ levels were assessed at 36, 72, and 90 months after baseline assessment. Results: The prognostic performance of U-p53AZ to predict the progression to AD from preclinical or prodromal AD was high, with area under the receiver operating characteristic curve (AUC) values close to or above 0.90. Furthermore, U-p53AZ predicted the progression to AD more than 6 years prior to symptom onset with positive and negative predictive values of about 90%. Additionally, the estimated prognostic performance of U-p53AZ was superior to other main risk factors (i.e., age, sex, and either alone or in combination with amyloid status. Furthermore, U-p53AZ had high diagnostic performance to differentiate cognitively normal individuals from those with AD (AUC values >0.88). Conclusion: These findings support the use of U-p53AZ as a prognostic blood-based biomarker accurately predicting the progression to AD dementia during the preclinical and prodromal stages at least 6 years before receiving the clinical diagnosis of AD dementia.

Background: Ongoing research seeks to identify blood-based biomarkers able to predict the onset and progression of Alzheimer’s disease (AD). A potential biomarker is the unfolded conformational variant of p53, previously observed in individuals in the prodromal and clinical AD stages. In this retrospective study, we compare diagnostic and prognostic performances of measures of the amyloid β load with those of a conformational variant of U-p53 in plasma samples from individuals participating in the Australian Imaging, Biomarkers and Lifestyle (AIBL) cohort. Methods: Immunoprecipitation (IP) followed by liquid chromatography (LC) tandem mass spectrometry (MS/MS) and protein sequencing in plasma samples from the AIBL study identified the clinically relevant AZ 284 ^® peptide, representing a measure of the U-p53 conformational variant (U-p53 ^AZ ). Based on U-p53 ^AZ quantification via IP/LC electrospray ionisation-coupled MS/MS (AlzoSure ^® Predict test) on 515 samples from 482 individuals from the AIBL cohort, the predictive performance of U-p53 ^AZ was assessed and compared with amyloid load as measured by amyloid β-positron emission tomography (Aβ-PET). Its predictive performance was determined at 36, 54, 72 and 90 months following baseline assessment. Results: U-p53 ^AZ was able to identify individuals with AD dementia with an area under the receiver operating characteristic curve (AUC) of 99%. U-p53 ^AZ outperformed the conventional Aβ-PET measures in predicting the onset of AD dementia both from preclinical (AUC=98%) and prodromal stages (AUC=89%), even 90 months prior to onset (AUC=99%). Additionally, the estimated predictive performance of U-p53 ^AZ was superior (AUC ≥98%) to other risk factors (i.e., gender, Aβ-PET and APOE ε4 allele status) in identifying individuals at high risk for progression to AD. Conclusion: These findings support use of U-p53 ^AZ as blood-based biomarker predicting if individuals, at both asymptomatic and MCI stages, would progress to AD at least six years prior to the onset of clinical AD dementia.

Despite the increasing number of individuals affected by Alzheimer’s disease (AD) every year, no effective therapy has been developed to treat this neurodegenerative disease yet. The current methods for AD diagnosis are effective for clinical confirmation of the disease only when symptoms become apparent, years after molecular damage started within the patients’ brains. As higher expression of a conformationally altered p53 has been correlated with AD, we developed a mass spectrometry-based method for highly sensitive, specific, and reproducible quantification of a p53 conformational variant in plasma samples of patients with known clinical outcome. In particular, we tested the prognostic performance of an AD-specific 2D3A8-immunoselected p53 peptide (AZ 284™) in different sets of individuals progressing from both cognitively unimpaired (CU) and mild cognitive impairment (MCI) patients progressing to AD dementia. Our data showed that quantitative analysis of AZ 284™ is a reliable tool for predicting AD progression up to 6 years prior to dementia onset with AUC >90%. Taken together, these results support the implementation of p53 conformational variant quantification as an affordable and powerful diagnostic tool for early, non-invasive AD diagnosis.

INTRODUCTION: Alzheimer’s Disease (AD) is a major public health challenge. An AD-specific unfolded form of the p53 protein was identified (U-p53 ^AZ ) and data from animal studies suggests it colocalizes with pTau, in neurofibrillary tangles (NFT) METHODS: Brain samples of patients with AD, cognitively unimpaired non-AD, and with fronto-temporal dementia (FTD) are being tested, comparing the pattern of U-p53 ^AZ accumulation (using the antibody 2D3A8, developed by Diadem SpA) with accumulation of pTau, beta-amyloid, and TDP-43. RESULTS: U-p53 ^AZ accumulates in brain samples from AD, colocalizes with pTau in the NFT, with a small degree of accumulation in neuritic plaques (NP). The intensity of staining correlates with the pTau staining and Braak staging. No staining is observed in samples from cognitively unimpaired non-AD and FTD. DISCUSSION: This study provides further support to the hypothesis that U-p53 ^AZ is a player in AD pathology, in link with pTau accumulation and Braak staging.