Microbial Trojan Horses: Virulence Factors as Key Players in Neurodegenerative Diseases

Abstract

Changes in population demographics indicate that the elderly population will reach 2.1 billion worldwide by 2050. In parallel, there will be an increase in neurodegenerative diseases such as Alzheimer's and Parkinson's. This review explores dysbiosis occurring in these pathologies and how virulence factors contribute to the worsening or development of clinical conditions, and it summarizes existing and potential ways to combat microorganisms related to these diseases. Microbiota imbalances can contribute to the progression of neurodegenerative diseases by increasing intestinal permeability, exchanging information through innervation, and even acting as a Trojan horse affecting immune cells. The microorganisms of the microbiota produce virulence factors to protect themselves from host defenses, many of which contribute to neurodegenerative diseases. These virulence factors are expressed according to the genetic composition of each microorganism, leading to a wide range of factors to be considered. Among the main virulence factors are LPS, urease, curli proteins, amyloidogenic proteins, VacA, and CagA. These factors can also be packed into bacterial outer membrane vesicles, which transport proteins, RNA, and DNA, enabling distal communication that impacts various diseases, including Alzheimer's and Parkinson's.

Keywords: gut–brain axis; neurodegenerative disease; outer membrane vesicles; virulence factors.

Figure 1

Summary of the complex pathophysiology of Alzheimer’s disease. The disease is characterized by a series of changes in the brain, such as the deposition of β-amyloid plaques and the formation of neurofibrillary tangles. The irregular unfolding of amyloid precursor proteins (APPs) and ApoeE generates the deposition of β-amyloid plaques, while a high activation of the GSK-3β enzyme promotes the hyperphosphorylation of Tau proteins, which polymerizes to form the tangles. These abnormal protein aggregates promote astrocyte reactivity, microglia activation, increased Ca⁺ influx, increased pro-inflammatory factors, decreased synapses, and neuronal death. Throughout the lives of patients, the main cognitive symptoms are dementia, memory deficit, changes in behavior, and inability to perform daily tasks.

Figure 2

Mechanisms that lead to neuronal death in Parkinson’s Disease. In the midbrain region, more specifically in the substantia nigra, the red arrows indicate a dense region with dopaminergic neurons, while the gray arrow indicate a decrease in dopaminergic neurons due deposit of aggregated proteins such as α-synuclein forms Lewy bodies, ultimately leading to cell death and causing a decline in the number of dopaminergic neurons. Consequently, there is a decrease in the number of dopaminergic synapses and the hyperactivation of microglia and an increase in pro-inflammatory cytokines and activated immune cells. Among the symptoms, patients present motor deficits, such as tremors and rigidity, and non-motor symptoms, such as gastrointestinal problems and depression.

Figure 3

H. pylori OMVs and the complex ways they could interfere with neurodegenerative diseases. OMVs play a fundamental role in the formation of biofilm and microbial resistance, favoring bacteria and worsening infections. In addition, these vesicles, due to their content of virulence factors, are internalized near the junctions of gastric epithelial cells and generate an increase in pro-inflammatory cytokine IL-8, apoptosis, the rupture of gastric epithelial cell–cell junctions, vacuolization, and the formation of micronuclei. Reaching the bloodstream and through the vagus nerve, OMVs can cross the blood–brain barrier and cause a homeostatic imbalance in cells, mainly astrocytes, which acquire a pro-inflammatory profile, leading to the recruitment of immune cells, decreased synapses, and the death of neurons.

Figure 4

Mechanism of virulence factors in neurodegenerative diseases. The figure illustrates the mechanisms by which the LPS, a key membrane component of Gram-negative bacteria, contributes to neuroinflammation and the progression of neurodegenerative diseases such as Alzheimer’s and Parkinson’s. In addition to LPSs, other bacterial virulence factors, such as ureases, VacA, CagA, hemolysins, fimbriae, catalase, and amyloid proteins, are also involved in the pathogenesis of NDs. Ureases, VacA, and CagA can induce neurotoxic and pro-inflammatory effects by inducing hyperphosphorylation of tau protein, indicated by the black and yellow dashed line. Meanwhile, bacterial amyloid proteins can accelerate the aggregation of eukaryotic amyloid proteins, such as Aβ and α-synuclein, indicated by the purple and pink dashed line. The red line indicates proteins such as urease, hemolysins, or PSMα and SCFA can generate reactive astrogliosis, with a pro-inflammatory profile in the cells. The pink dashed line also indicates that amyloid proteins, ureases and catalase can contribute to the increased deposition of α-synuclein.