Natural Products as the Potential to Improve Alzheimer’s and Parkinson’s Disease

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TL;DR

This narrative review summarizes the molecular mechanisms of Alzheimer's and Parkinson's diseases—focusing on β-amyloid, tau, and α-synuclein pathology, mitochondrial dysfunction, and neuroinflammation—and evaluates 16 natural products (e.g., Reynoutria multiflora, Theobroma cacao, Panax ginseng) for their neuroprotective effects in preclinical models. The reviewed natural compounds show potential through antioxidant, anti-inflammatory, and autophagy-modulating pathways, but the authors note that current FDA-approved drugs only manage symptoms and have significant adverse effects. The clinical significance is that natural products may offer safer, multi-target therapeutic candidates, though further safety and clinical trials are needed before translation to humans.

Full summary

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**Background:** Neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD) involve progressive nerve cell death in the brain and spinal cord. AD affects approximately 24 million people worldwide, with sharply increasing incidence in those over 65 years. PD is the second most common neurodegenerative disease, with an incidence of 1–2 per 1000 people and affecting 1% of the population over 60. The exact causes remain unknown, but evidence points to a complex interplay of environmental and genetic factors. AD is primarily associated with β-amyloid plaque formation and neurofibrillary tangles from hyperphosphorylated tau in the hippocampus. PD is linked to Lewy bodies formed by abnormal aggregation of α-synuclein in the substantia nigra. Additional mechanisms include neuroinflammation, oxidative stress, and mitochondrial dysfunction. Current FDA-approved medications—including donepezil (1996), galantamine (2001), rivastigmine (2000), memantine (2003), levodopa (1975), COMT inhibitors, MAO-B inhibitors, and dopamine agonists—only alleviate or slow symptom progression and carry significant adverse effects such as nausea, dyskinesias, hallucinations, and cognitive decline. This underscores the need for safer, more effective therapies derived from natural products.

**Methods:** The authors conducted a literature search of the National Center for Biotechnology Information (NCBI) database using the MeSH terms "Alzheimer's disease," "Parkinson's disease," and "Natural products." No time restriction was applied. Papers were selected if they specified mechanisms of action through both in vitro and in vivo studies. Exclusion criteria included papers not containing the specified keywords, review articles covering multiple diseases, case reports, clinical trials, literature reviews, and irrelevant abstracts or dissertations. Sixteen papers were ultimately selected for detailed review.

**Key Results:** The 16 natural products reviewed demonstrated neuroprotective effects through several mechanisms. (1) Antioxidant pathways: Reynoutria multiflora (100–200 μM in vitro; 20 mg/kg in vivo) restored FGF2 and BDNF expression and activated FGF2-Akt and BDNF-TrkB signaling. Achillea fragrantissima (up to 34.7 μM) inhibited phosphorylation of SAPK/JNK, ERK 1/2, MEK1, and CREB. Theobroma cacao (30 μg/mL epicatechin, 10 μg/mL catechin, 170 μg total polyphenols) activated the BDNF survival pathway. Salvia miltiorrhiza (100–400 μM) activated Nrf2 nuclear translocation to increase HO-1 and induced Akt phosphorylation. Asparagus racemosus (18 mg/kg) reduced lipid peroxidation and protein carbonyl while improving GPx activity and GSH content. Opuntia ficus-indica (1 mg/mL in yeast; 0.06% in Drosophila; 100–2000 μg/mL in vitro) inhibited fibrillogenesis of both Aβ42 and α-syn. Gardenia jasminoides (10–50 mg/kg) suppressed neuroinflammation via PI3K/AKT signaling. Vitis labrusca (12.5–50 μM in vitro; 60 mg/kg in vivo) reduced oxidative stress and improved mitochondrial dysfunction via PI3K/Akt. Paullinia cupana (10–50 mg/mL) reduced intracellular ROS and autophagosome accumulation while increasing SOD-3 and HSP-16.2 expression. Tussilago farfara (1.25–10 μM in vitro; 5 mg/kg in vivo) activated the Nrf2/HO-1 pathway. Panax ginseng (6.25–200 μg/mL) restored ER and mitochondrial functions via HDAC6 and HSP90. Polygala tenuifolia (12.5–100 μM) maintained mitochondrial function and regulated caspase-3 and tyrosine hydroxylase. Alpinia oxyphylla (12–400 μM in vitro; 10–20 mg/kg in vivo) acted through Akt-GSK3β and Nrf2-Keap1-HO-1 pathways. Paeonia suffruticosa (0.75–1.5 μM) decreased ROS and increased SOD activity and anti-apoptotic protein expression. Paeonia lactiflora (0.1–10 μM) regulated mitochondrial membrane potential and Bcl-2/Bax signaling. Cynanchum otophyllum (6.5–25 μg/mL in vitro; 25–100 mg/kg in vivo) activated the PPARα-TFEB pathway, reducing β-amyloid and tau aggregates and inhibiting microgliosis and astrocytosis in 3xTg AD mice.

**Clinical Implications:** The reviewed natural products demonstrate multi-target mechanisms—including antioxidant, anti-inflammatory, mitochondrial protection, and autophagy modulation—that address core pathological features of AD and PD. Unlike current FDA-approved drugs that only manage symptoms and carry adverse effects, these natural compounds may offer safer alternatives with broader therapeutic potential. However, the authors emphasize that natural products require substantially more research to establish safety profiles before advancing to clinical trials or regulatory approval. The fact that many of these mechanisms (anti-inflammatory, antioxidant, autophagy) are not disease-specific suggests that natural products with established efficacy in other conditions may also be applicable to neurodegenerative diseases. The authors recommend establishing daily intake guidelines for natural products that can be consumed as food for more effective preventive or therapeutic use.