Higher Frontal Cortex Angiotensin Type 2 Receptor‐Interacting Protein ( ATIP ) Levels Are Associated With a Lower Amyloid‐Beta Burden in Postmortem Brains of Older Adults With Alzheimer's Disease

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ABSTRACT Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by amyloid‐β (Aβ) and tau accumulation. Dysregulation of the brain renin‐angiotensin system, particularly hyperactivation of the angiotensin II type‐1 receptor, contributes to AD pathogenesis. In contrast, activation of the angiotensin II type‐2 receptor (AT 2 R) has been linked to neuroprotection and reduced Aβ accumulation. However, the underlying mechanisms of AT 2 R‐related Aβ reduction and the role of AT 2 R‐interacting protein (ATIP), also known as AT 2 R‐binding protein, remain unclear. We aimed to explore the relationship between ATIP and Aβ and tau pathologies as well as brain AT 2 R protein levels in older adults with AD. Using TOMAHAQ, a method that enables precise examination of numerous peptides across various samples in a single mass spectrometry analysis, we identified a specific human tryptic peptide that enables ATIP quantification. We applied this method to postmortem frontal‐cortex samples to measure ATIP levels. Sixty individuals with AD were included, half of whom were users of angiotensin receptor blockers (ARBs). The ATIP peptide was quantifiable in 12 participants. Among these individuals, higher ATIP levels were associated with lower Aβ burden in the frontal‐cortex and across multiple brain regions. This association remained significant after adjustment for age and ARB use. In contrast, ATIP levels were not significantly associated with AT 2 R, which was quantified using TOMAHAQ. This suggests that the relationship between ATIP and Aβ burden may not depend on differences in AT 2 R abundance. Although causality cannot be established, these findings may suggest a potential protective role for ATIP in AD that warrants further investigation.

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