Nut consumption as a therapeutic strategy to preserve brain function, attenuate neuropathology, and modulate cross-tissue microRNAs in a mouse model of Alzheimer's disease

Abstract

Nutritional modulation of brain metabolism is emerging as a key strategy for preventing Alzheimer’s Disease (AD), with potential to influence key pathologies such as Aβ accumulation, tau phosphorylation, and neuroinflammation. However, the biological mechanisms linking diet, metabolism, and AD remain poorly understood. The aim of this study is to investigate the neuroprotective effects of a nuts-enriched diet (NED) on AD-like pathology using APPswe/PS1dE9 (APP) transgenic mice, focusing on cognition, neuroinflammation, Aβ burden, and the potential regulatory role of circulating and brain-tissue specific microRNA (miRNA). APP and wild-type (WT) male mice were fed either a control diet (CD) or NED providing 10% of total energy from mixed nuts. Behavioral performance, Aβ deposition, glial activation, and synaptic integrity were assessed, alongside miRNA profiling in serum, cortex, and hippocampus. In APP mice, NED enhanced hippocampal-dependent memory, reduced microglia and astrocyte reactivity, decreased cortical and hippocampal Aβ plaque burden, and preserved dendritic spine density. Multi-compartment miRNA analyses revealed that NED modulated several AD-relevant miRNAs involved in insulin signaling, neuroinflammation, and synaptic function. These miRNA alterations correlated with improved cognitive outcomes and attenuated neuropathology, suggesting coordinated metabolic and molecular reprogramming in response to dietary intervention. A nuts-enriched diet exerted significant neuroprotective effects in an AD mouse model, potentially mediated through coordinated miRNA regulation and related metabolic pathways. These findings support nut consumption as a feasible nutrition-based strategy for AD prevention, and identify candidate miRNAs that may serve as biomarkers or mechanistic mediators at the intersection of diet, metabolism, and neurodegeneration.