Minor Phytocannabinoids as Candidate Multi-Target Modulators of Endoplasmic Reticulum Stress-Linked Proteostasis Failure in Alzheimer's Disease: A Mechanistic Review.

Lee H.; Park S.; Chae H. · Biomolecules · 2026

**Background & Methods** This is a mechanistic review examining whether five minor phytocannabinoids from Cannabis sativa L. (CBG, CBC, CBN, CBDV, THCV) warrant investigation as therapeutic modulators of endoplasmic reticulum (ER) stress and proteostasis failure in Alzheimer's disease. The authors organized evidence around four converging pathological processes: calcium dyshomeostasis, mitochondrial dysfunction and oxidative stress, neuroinflammation, and autophagic impairment, with separate evaluation of unfolded protein response (UPR) marker changes. **Key Findings** • **Distinct cannabinoid target profiles**: Minor phytocannabinoids demonstrate overlapping but distinct molecular mechanisms involving cannabinoid receptors, transient receptor potential (TRP) channels, peroxisome proliferator-activated receptors, mitochondrial pathways, and inflammatory signaling, suggesting multi-target modulation of ER stress-linked proteostasis failure. • **Compound-specific associations**: CBN shows primary association with mitochondrial stress pathways; CBG with oxidative and inflammatory pathways; THCV with inflammatory signaling; CBC and CBDV with TRP-related calcium signaling and autophagy. CBDV and CBG demonstrate UPR marker changes in non-neuronal cells, though functional relevance to AD remains uncertain. • **Limited direct evidence**: While these compounds target interconnected pathways implicated in AD pathogenesis, direct evidence for ER stress modulation and UPR normalization in AD-relevant systems remains limited, and CBN's hypothetical involvement in ER-mitochondria signaling requires validation. **Dosage & Administration** Not reported. **Safety & Adverse Effects** Not reported. **Evidence Quality** This review represents a mechanistic synthesis of preclinical literature rather than clinical evidence. Significant limitations include: (1) lack of direct UPR-modulating evidence in AD models; (2) primarily in vitro and non-neuronal cell data; (3) absence of in vivo pharmacokinetic studies in brain tissue; (4) uncertain functional direction and AD relevance of observed UPR changes; and (5) no clinical trial data. The authors explicitly state that validation in AD-relevant neuronal cultures, organoid models, in vivo studies, and pharmacokinetic investigations is required before therapeutic potential can be established. This represents early-stage mechanistic evidence suitable for hypothesis generation rather than clinical application.

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