Evolution of Alzheimer's Disease Therapeutics: From Conventional Drugs to Medicinal Plants, Immunotherapy, Microbiotherapy and Nanotherapy

Abstract

Alzheimer's disease (AD) represents an escalating global health crisis, constituting the leading cause of dementia among the elderly and profoundly impairing their quality of life. Current FDA-approved drugs, such as rivastigmine, donepezil, galantamine, and memantine, offer only modest symptomatic relief and are frequently associated with significant adverse effects. Faced with this challenge and in line with advances in the understanding of the pathophysiology of this neurodegenerative condition, various innovative therapeutic strategies have been explored. Here, we review novel approaches inspired by advanced knowledge of the underlying pathophysiological mechanisms of the disease. Among the therapeutic alternatives, immunotherapy stands out, employing monoclonal antibodies to specifically target and eliminate toxic proteins implicated in AD. Additionally, the use of medicinal plants is examined, as their synergistic effects among components may confer neuroprotective properties. The modulation of the gut microbiota is also addressed as a peripheral strategy that could influence neuroinflammatory and degenerative processes in the brain. Furthermore, the therapeutic potential of emerging approaches, such as the use of microRNAs to regulate key cellular processes and nanotherapy, which enables precise drug delivery to the central nervous system, is analyzed. Despite promising advances in these strategies, the incidence of Alzheimer's disease continues to rise. Therefore, it is proposed that achieving effective treatment in the future may require the integration of combined approaches, maximizing the synergistic effects of different therapeutic interventions.

Keywords: Alzheimer’s disease; fecal microbiota transplantation; immunotherapy; medicinal plants; miRNAs; nanotechnology; probiotics.

Figure 1

The pathophysiology of Alzheimer’s disease.

Figure 2

Multi-target effects of different cholinesterase inhibitors. Donepezil, galantamine, and rivastigmine show neuroprotective effects by decreasing Aβ levels, inhibiting GSK3β, and, therefore, pTau reduction. They also reduce oxidative stress and excitotoxicity levels.

Figure 3

Delivery of pharmaceutical agents across the BBB into the CNS. I. INVASIVE. (A). The use of noxious agents, hyperosmotic solutions or ultrasound reduces endothelial cells in the brain [342]. This is achieved by disrupting tight junctions, compromising the BBB; (B). Injecting drugs directly into the cerebrospinal fluid is a way of delivering pharmaceutical agents to the central nervous system. This can be done through a lumbar puncture or an implanted device [343,344]. II. NON-INVASIVE: (C). A drug may be combined with lipoids for brain delivery. This approach may be constrained by the trade-off between increased lipophilicity and increased biodistribution. This technique necessitates that the treatment emulates endogenous ligands. Glycosylation enhances drug and peptide transport to the brain while improving stability. Other processes, such as cyclization, halogenation, methylation, or unnatural linkers, can be used to modify BBB-crossing drugs [345,346]; (D). Viral vectors can cross the BBB by transcytosis or temporary BBB disruption. Transcytosis occurs via receptor-mediated vascular endothelial cells of the brain. The temporary disruption of the BBB permits the vector to gain access to the interstitial regions of the CNS via paracellular transport [347,348]; (E). Surface modifications could help exosomes cross the BBB. Exosomes can be functionalized with biomolecules and polymers without affecting their activity. Chemical modifications are attractive due to synthesis, yield, and chemical reaction [349,350,351]; (F). Intranasal (IN) administration delivers drugs directly to the CNS via the nasal cavity. This method delivers the agent directly to the CNS, reducing exposure and adverse effects. Therapeutic agents reach the central nervous system rapidly [352,353,354]; (G). Four different adenosine receptors (A1, A3, A2A, and A2B) can regulate the BBB permeability. A2A regulates BBB permeability via actin-cytoskeletal reorganization, affecting tight junctions [355,356,357,358]; (H). Microbubble-enhanced diagnostic ultrasound (MEUS) facilitates drug passage through the BBB in glioma patients. Principal proteins at the BBB transluminal junctions are claudins, occludin, and JAMs. The use of ultrasound and microbubbles has been shown to suppress the expression of these proteins at the translaminar junctions, thereby opening the BBB in a relatively short period of time without causing damage to normal brain tissue [359].

Figure 4

Applications of nanotechnology in the treatment of AD: Nanoparticles, due to their small size, can more effectively cross the BBB. Lipid-soluble nanoparticles, such as liposomes, can be used to transport drugs through the BBB, thus increasing the drugs’ bioavailability. Metallic nanoparticles, such as gold nanoparticles, have been used to inhibit the formation of Aβ aggregates, inhibiting the formation of neuritic plaques. Covalent bonding of drugs with specific nanoparticles can improve the active uptake of the bonded drugs by the endothelial cells, increasing their uptake into the brain and facilitating drug targeting. Created with BioRender.com. BBB, blood–brain barrier; APP, amyloid precursor protein; Aβ, Amyloid beta; Au, Gold; C, Carbon.