Investigating the Mechanistic Role of piRNA Dysregulation in Amyloid-beta Toxicity and Tau Pathology in Alzheimer’s Disease Pathophysiology: Implications for Therapeutic Targets
Soroush Taherkhani1*, Zeynab Sharifiaghdam1, Parnian Amani2
1Department of Physiology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.
2Department of Physiology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.
3Department of Biology, Qaemshahr Branch, Islamic Azad University, Qaemshahr, Iran.
*Corresponding Author: Soroush Taherkhani, Department of Physiology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.
DOI: https://doi.org/10.58624/SVOANE.2026.07.027
Received: June 03, 2026
Published: August 17, 2026
Citation: Taherkhani S, Sharifiaghdam Z, Amani P. Investigating the Mechanistic Role of piRNA Dysregulation in Amyloid-beta Toxicity and Tau Pathology in Alzheimer’s Disease Pathophysiology: Implications for Therapeutic Targets. SVOA Neurology 2026, 7:4, 184-209. doi.org/10.58624/ SVOANE.2026.07.027
Abstract
Alzheimer’s disease (AD) represents the most prevalent neurodegenerative disorder worldwide, characterized by progressive cognitive decline, amyloid-beta (Aβ) plaque deposition, and neurofibrillary tangle formation. While the amyloid cascade and tau propagation hypotheses have dominated the field for decades, emerging evidence implicates epigenetic mechanisms, particularly PIWI-interacting RNAs (piRNAs), in the early pathogenesis of sporadic AD. This review synthesizes current knowledge regarding piRNA dysregulation in AD, examining mechanistic links between piRNA loss, transposable element activation, Aβ toxicity, and tau pathology while evaluating therapeutic implications. We first discuss how AD associated stressors, including oxidative stress and mitochondrial dysfunction, alter piRNA expression profiles in vulnerable brain regions such as the hippocampus and cortex. Next, we examine mechanistic convergence points: aberrant piRNAs may de-repress transposable elements (e.g., LINE-1), triggering cytosolic DNA sensing pathways and neuroinflammation that exacerbate Aβ aggregation. Simultaneously, piRNA imbalance is hypothesized to disrupt post-transcriptional networks governing microtubule-associated protein tau, potentially via competitive binding with microRNAs or through PIWI-clade proteins that directly interact with tau kinases (e.g., GSK-3β, CDK5). Additionally, we evaluate evidence linking piRNA-mediated epigenetic modulation of BACE1 and MAPT promoters to sustained amyloidogenic and tauogenic cascades. Key databases including PubMed, Google Scholar, and Europe PMC were searched for relevant publications from 2017–2026. Multiple studies demonstrate significant piRNA dysregulation in human AD brains and cerebrospinal fluid, with specific piRNA signatures correlating with Braak staging and amyloid/tau PET biomarkers. Mechanistically, Aβ-induced oxidative stress disrupts PIWI protein expression, leading to LINE-1 retrotransposon derepression, genomic instability, and feedforward amplification of amyloidogenic processing. Tau pathology further exacerbates piRNA depletion through PIWI-piRNA complex mislocalization, creating a vicious cycle of epigenetic dysregulation and neurodegeneration. piRNA dysregulation represents a convergent node linking Aβ and tau pathologies with downstream neuroinflammation via cGAS-STING activation. Restoring piRNA function through synthetic mimics, PIWI stabilizers, or CRISPR activation of piRNA clusters offers novel therapeutic avenues for disease modification in AD.
Keywords: PIWI-interacting RNA; Alzheimer’s disease; Amyloid-beta; Tau pathology; LINE- 1; BACE1; Retrotransposon; CRISPR; Neuroinflammation
