Brain-Gut-Microbiota Axis in Alzheimer’s Disease

Abstract

Disturbances along the brain-gut-microbiota axis may significantly contribute to the pathogenesis of neurodegenerative disorders. Alzheimer’s disease (AD) is the most frequent cause of dementia characterized by a progressive decline in cognitive function associated with the formation of amyloid beta (Aβ) plaques and neurofibrillary tangles. Alterations in the gut microbiota composition induce increased permeability of the gut barrier and immune activation leading to systemic inflammation, which in turn may impair the blood-brain barrier and promote neuroinflammation, neural injury, and ultimately neurodegeneration. Recently, Aβ has also been recognized as an antimicrobial peptide participating in the innate immune response. However, in the dysregulated state, Aβ may reveal harmful properties. Importantly, bacterial amyloids through molecular mimicry may elicit cross-seeding of misfolding and induce microglial priming. The Aβ seeding and propagation may occur at different levels of the brain-gut-microbiota axis. The potential mechanisms of amyloid spreading include neuron-to-neuron or distal neuron spreading, direct blood-brain barrier crossing or via other cells as astrocytes, fibroblasts, microglia, and immune system cells. A growing body of experimental and clinical data confirms a key role of gut dysbiosis and gut microbiota-host interactions in neurodegeneration. The convergence of gut-derived inflammatory response together with aging and poor diet in the elderly contribute to the pathogenesis of AD. Modification of the gut microbiota composition by food-based therapy or by probiotic supplementation may create new preventive and therapeutic options in AD.

C‐type lectin‐like receptor 2 and zonulin are associated with mild cognitive impairment and Alzheimer's disease

“…2 Alterations in the composition of gut microflora may result in increased permeability of gut barrier, thereby impairing blood-brain barrier and promoting neuroinflammation, and ultimately leading to neurodegeneration. 2 Alterations in the composition of gut microflora may result in increased permeability of gut barrier, thereby impairing blood-brain barrier and promoting neuroinflammation, and ultimately leading to neurodegeneration.…”

Outer membrane vesicles enhance tau phosphorylation and contribute to cognitive impairment

“…Recent research techniques and results focused on the interaction of the gut microbiota (GM) with the central nervous system ("microbe-gut-brain axis") (Kowalski & Mulak, 2019;Roubalova et al, 2019), and AD has been associated with an abnormal GM composition (Bostanciklioğlu, 2019;Doulberis et al, 2019). GM affects the nervous system including vagal nerve and adrenergic nerve activation, as well as the production of neurotransmitters or by evoking the enteroendocrine cells, enterochromaffin cells and the mucosal immune system to relay gut-brain signalling (Collins, Surette, & Bercik, 2012;Li et al, 2018); GM also regulates the release of cortisol to govern the activation state of brain microglia and effect cytokine release, as well as influence the levels of pro-inflammatory cytokines and anti-inflammatory cytokines in the blood to affect the central nervous system (Malan-Muller et al, 2018;Osadchiy, Martin, & Mayer, 2019).…”

Advance of sporadic Alzheimer's disease animal models

“…The cholinergic system is involved in critical physiological processes, such as attention, learning, memory, stress response, wakefulness and sleep, and sensory information. While an extensive loss of forebrain cholinergic neurons accompanied by a reduction of the cholinergic fiber network were found in the cortical mantel and hippocampus of AD patients 15,16 Gut microbiota Alterations in the gut microbiota composition induce increased permeability of the gut barrier and immune activation leading to systemic inflammation, which in turn may impair the blood-brain barrier and promote neuroinflammation, neural injury, and ultimately neurodegeneration 17,18 Lipid metabolism abnormalities Cholesterol metabolic abnormalities could accelerate the formation of Aβ and phosphorylated Tau protein, oxidative stress, neuronal apoptosis, and microglial activation 19,20 Autophagy dysfunction Autophagy has a pivotal role in the disposal of Aβ and Tau aggregates. The reduction of Akt signaling redeems GSK3β from inhibition which in addition to causing Tau phosphorylation and aggregation, it disrupts autophagy signaling thus reducing the clearance of amyloid precursor 21,22 Insulin resistance state Brain glucose deficit showed significant memory impairments, reduction of synaptic long-term potentiation, increased Tau phosphorylation, Aβ deposition, and loss of neurons 3 Synapse dysfunction The loss of synapses in the affected brain regions correlates best with cognitive impairment in AD patients and has been considered as the early mechanism that precedes neuronal loss 9,23 Metal ions disorder The dysfunction of metal ions can promote the development of pathological changes, leading to the accumulation of misfolded Aβ and phosphorylated Tau protein, oxidative stress, and DNA oxidative damage 24,25 Abbreviations: Aβ, β-amyloid; AD, Alzheimer's disease; IL, interleukin; GSK3, glycogen synthase kinase 3β; ROS, reactive oxygen species; TNF-α, tumour necrosis factor α.…”

“…While nearly 95% of patients with AD are classified as sAD, which are caused by a combination of genetic factors and environmental risk factors without documented familial history of AD . Various hypotheses of mechanisms for sAD include deposition of β‐amyloid (Aβ), hyperphosphorylation of Tau, oxidative stress, neuroinflammation, cholinergic neuron degeneration, gut microbiota disorders, lipid metabolism abnormalities, autophagy dysfunction, insulin desensitization/resistance state, synapse dysfunction, and metal ions disorders in the brain (summarized in Table ).…”