Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and memory loss, impacting millions of people globally [1]. Despite advances in the understanding of AD pathology—including amyloid-beta (Aβ) plaques, tau hyperphosphorylation, and neuroinflammation—effective therapies are urgently needed [2]. Withania somnifera (Ashwagandha), a traditional Ayurvedic herb, shows promise in AD management due to its antioxidant, anti-inflammatory, and neuroprotective properties. Key bioactive compounds (Figure 1), such as withanolides and withaferin A, help reduce oxidative stress, inhibit plaque formation, and modulate inflammation [3].

Withaferin A (WA) from Withania somnifera shows potential for AD treatment through multiple mechanisms. It reduces Aβ aggregation, suppresses NF-κB and Hsp90, and inhibits iNOS, thereby decreasing Aβ-induced neurotoxicity. WA enhances cognitive function by boosting neuroprotective proteins (Hsp27, Hsp70), lowering tau aggregation, and modulating microglial activity [4]. Berghe et al. demonstrated that WA alleviates TAR DNA-binding protein-43, a pathological hallmark of AD, while boosting the autophagic marker LC3BII and its activation of Nrf2, which enhances antioxidant defenses and preserves synaptic function [5]. Aβ deposition is a hallmark of AD, and withanolide A from Withania somnifera demonstrates therapeutic potential by reducing Aβ secretion, aggregation, and neurotoxicity in APP-transfected cells. WA also increases α-secretase and insulin-degrading enzyme (IDE) activity, thereby promoting Aβ breakdown [6]. Withanamide binds specifically to Aβ (25-35), limiting fibril formation and neuronal death [7]. Additionally, withanolide A and withanamides enhance antioxidant enzymes, reducing oxidative stress and mitochondrial dysfunction, positioning them as promising AD treatments [7].
Current AD treatments, such as acetylcholinesterase (AChE) inhibitors and NMDA receptor antagonists, offer only temporary cognitive relief. WA from Withania somnifera shows promise as an AD therapy by restoring cholinergic markers, inhibiting AChE and butyrylcholinesterase (BuChE), and enhancing acetylcholine levels. Studies show that WA boosts cholinergic neurotransmission and improves cognitive function without affecting other receptors. At 50 mg/kg, WA provides neuroprotection by increasing dopamine levels, potentially reducing motor deficits [8]. In AD, Aβ fibrils activate microglia, triggering NF-κB and the NLRP3 inflammasome, which release pro-inflammatory cytokines (Figure 2) [9]. WA effectively inhibits NF-κB by targeting IKKβ, thereby reducing proinflammatory mediators such as TNF-α and IL-1. WA also modulates nitric oxide and COX-2 levels, inhibits iNOS, and decreases VCAM-1 and ICAM-1 expression, thus curbing microglial inflammation and potentially reducing Aβ accumulation and neurodegeneration. WA disrupts the CDC37-HSP90 complex and influences AD-related proteins such as AKT and IKK, underscoring its therapeutic potential in AD treatment [10].

Nanoparticle-based drug delivery holds promise for AD treatment by enabling targeted transport across the blood-brain barrier (BBB). Withania somnifera extracts rich in withanolides were shown by Sehgal et al. to reduce H₂O₂- and amyloid-induced cytotoxicity in AD mouse models, enhancing lipoprotein kinase levels [11]. Withaferin A-loaded nanoparticles by Madhu et al. provided sustained neuroprotection with efficient release [12]. Mancini et al. developed mApoE-PA-LIP nanoparticles that act as amyloid-beta "sinks", and enhance Aβ clearance [13]. Further large-scale trials are needed to confirm Ashwagandha's therapeutic potential in AD.

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