Exosome-based approaches in the management of Alzheimer's disease

Abstract

Alzheimer's disease (AD) has been the most extensively studied neurological disorders that affects millions of individuals globally and is associated with misfolding of proteins in the brain. Amyloid-β and tau are predominantly involved in the pathogenesis of AD. Therapeutic interventions and nanotechnological advancements are useful only in managing the AD symptoms and the cure for this disease remains elusive. Exosomes, originating from most cell and tissue types are regarded as a double-edged sword, considering their roles in the progression and treatment of AD. Exosomes can be manipulated as drug delivery vehicles for a wide range of therapeutic cargos-both small molecules and macromolecules. Herein, we review the roles of exosomes in the pathology, diagnosis, and treatment of AD and highlight their application as a drug carrier to the brain for AD treatment.

Keywords: Alzheimer's disease; Blood brain barrier; Drug delivery; Exosome; Gene therapy.

Fig. 1.

Pathophysiology of Alzheimer’s disease and role of exosomes in its development. Enzymatic degradation of amyloid precursor protein generates amyloid beta (Aβ), which is taken up by early endosomes and accumulates on the exosome surface. The release of exosomes containing Aβ into the synaptic cleft helps in the formation of senile plaques and blocks neurotransmission, leading to the development of AD. On the contrary, instability of microtubules in recipient neurons results in the release of tau and in the development of neurofibrillary tangles, which, in turn, cause damage to the neurons and receptors. Damaged neurons are unable to produce choline acetyltransferase (ChAT) and inhibit acetylcholine production by preventing the interaction of acetyl-CoA and choline. By preventing neurotransmission and causing damage to neuronal cells, Aβ and neurofibrillary tangles affect the functioning of the brain and lead to the progression of AD. Created with Biorender.com.

Fig. 2.

Structure of the blood–brain barrier (BBB) and cargo transport mechanism across blood and brain via the BBB. Brain neuronal cells are guarded against the entry of substances from the blood by the BBB. The BBB is made up of tight endothelial junctions surrounded by pericytes and astrocytes. The entry of drugs into the brain via the BBB is mediated through various pathways, such as adsorptive transcytosis, carrier-mediated transport, diffusion, efflux transport, paracellular transport, and receptor-mediated transcytosis. Created with Biorender.com. Partially adapted with permission from (Tang et al., 2019).

Fig. 3.

Biogenesis, source, and composition of exosomes. Exosomes, a class of small extracellular vesicles (EVs), originate from most cell types and are abundantly available in cell culture media and body fluids, such as plasma/serum, urine, and milk. Multivesicular bodies (MVBs) are generated from early endosomes by inward budding of the plasma membrane into the lumen. The exosomes are released into the extracellular space upon fusion of late MVBs with the plasma membrane. The exosomes once released into cell culture medium or body fluid can be isolated and utilized for disease management. Exosomes are made up of a lipid bilayer with distinctive protein identifiers, such as CD9, CD63, CD81, ALIX, and TSG101, and their cores are packed with various proteins, growth factors, enzymes and different nucleic acids. Partially adapted with permission from (Kandimalla et al., 2021b).