Genetic and environmental factors in Alzheimer's and Parkinson's diseases and promising therapeutic intervention via fecal microbiota transplantation

Abstract

Neurodegenerative diseases are characterized by neuronal impairment and loss of function, and with the major shared histopathological hallmarks of misfolding and aggregation of specific proteins inside or outside cells. Some genetic and environmental factors contribute to the promotion of the development and progression of neurodegenerative diseases. Currently, there are no effective treatments for neurodegenerative diseases. It has been revealed that bidirectional communication exists between the brain and the gut. The gut microbiota is a changeable and experience-dependent ecosystem and can be modified by genetic and environmental factors. The gut microbiota provides potential therapeutic targets that can be regulated as new interventions for neurodegenerative diseases. In this review, we discuss genetic and environmental risk factors for neurodegenerative diseases, summarize the communication among the components of the microbiota-gut-brain axis, and discuss the treatment strategy of fecal microbiota transplantation (FMT). FMT is a promising treatment for neurodegenerative diseases, and restoration of the gut microbiota to a premorbid state is a novel goal for prevention and treatment strategies.

Fig. 1. Associated markers or altered gene expression of AD.

Aβ, tau, TREM2 variants, targeted deletion of CX3CR1, and APOE4 variants have all been associated with AD (left column). The middle and right columns show the downstream effects.

Fig. 2. Associated markers or altered gene expression of PD.

α-Synuclein, LRRK2 mutation, PARKIN mutation, SNCA, and targeted deletion of GBA1 have all been associated with PD (left column). The middle and right columns show the downstream effects.

Fig. 3. Implications of metals in Aβ neurotoxicity.

APP binds to metals (Al, Cu, Fe, Mn, or Zn). Under acceleratory conditions, Aβ self-aggregates and forms several types of oligomers (SDS-soluble oligomers, Aβ-derived diffusible ligands, globulomers, and protofibrils) finally forming insoluble aggregates (amyloid fibrils), and tight binding to the surface of neurons and form fibrillar deposits.

Fig. 4. The microglia is a key mediator in the communication among microbiota-gut-brain axis.

Damaged neurons in the neurodegenerative brain release Aβ, tau, or α-synuclein, which accumulate and activate microglia. This leads to activation of senescent microglia that produce increased levels of pro-inflammatory cytokines and accelerating inflammatory cascade.