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Alzheimer's Disease and Tau: Pathogenic Mechanisms and Therapeutic Approaches

The influence of gut microbiota on brain function is being constantly investigated, and the mechanisms of the brain-gut-microbiota axis contribution to pathogenesis of stress-related conditions or brain disorders is being discovered.

The role of heparan sulfates in protein aggregation and their potential impact on neurodegeneration

The relative bacterial abundance correlated with the increase of cerebrospinal fluid markers of AD pathology. Poor diet is associated with reduced microbial diversity, contributing to the increased local and systemic inflammation in the elderly. A better understanding of the role of gut microbiota in the pathogenesis of AD and the close association between gut dysbiosis, increased intestinal permeability, and neurological dysfunction creates opportunity for potential therapeutic interventions. Antibiotic treatment offers another option for the gut microbiota modulation and can be applied to treat SIBO and intestinal colonization by pathogenic strains.

Surprisingly, in PD patients treatment of SIBO with rifaximin resulted not only in the improvement in gastrointestinal symptoms, but also motor fluctuations.

The Prion-Like Aspect of Alzheimer Pathology

Fecal microbiota transplantation is used in many animal models exploring pathogenetic mechanisms of neurodegenerative disorders. Its therapeutic potential has been reported in single cases of patients with PD, multiple sclerosis and autisms, but not AD so far. However, one of the most effective approaches to modify the gut microbiota is dietary intervention.

Food-based therapies may influence the gut microbiota composition or directly affect neuronal functioning in both the ENS and the CNS. There is increasing evidence for the gut microbiota contribution to the pathogenesis of AD Fig.

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The gut microbiota as the source of a large amount of amyloid, LPS, and other toxins, may contribute to systemic inflammation and disruption of physiological barriers. Bacteria or their products can move from the gastrointestinal tract and the oronasal cavity to the CNS, especially in the elderly. Bacterial amyloids may act as prion protein cross-seeding misfolding and enhancing native amyloid aggregation. Moreover, gut microbiota products may prime microglia, enhancing inflammatory response in the CNS, which in turn results in pathologic microglial function, increased neurotoxicity and impaired amyloid clearance.

The modulation of the gut microbiota composition can be used as a potential therapeutic target in AD. Up to now, the data on the role of gut microbiota in AD and other neurodegenerative disorders are based on preclinical or cross-sectional human studies. To enhance and forward AD research large-scale epidemiological studies investigating the complex interactions between genes, microbiota, diet, and aging should be conducted.

Some methodological issues concerning the evaluation of the microbiota composition and function including metabolomic profiling techniques need also to be considered. Moreover, the involvement of other microbiotas, apart from the microbiota in the gut and the oral and nasal cavities, in the pathophysiology of neurodegenerative disorders has not been explored so far. Finally, the effect of numerous confounding factors such as diet, concomitant diseases and drugs require a careful attention in the analyses. Author contributions: Karol Kowalski conceived and wrote the paper; Agata Mulak conceived and revised the paper; and both authors approved the final version of the manuscript.

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Title Author Keyword Volume Vol. All rights reserved. Keywords : Alzheimer disease, Amyloid, Blood-brain barrier, Gastrointestinal microbiome, Inflammation. Compromised Blood-Brain Barrier The blood-brain barrier formed by brain endothelial cells and pericytes separates the CNS from blood-derived molecules, pathogens, and cells.

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The fibril then breaks forming new seeds allowing for self-propagation of the process. The gut microbiota is known to upregulate local and systemic inflammation due to lipopolysaccharides LPS from pathogenic bacteria and synthesis of proinflammatory cytokines. Alterations in the gut microbiota composition may induce increased permeability of the intestinal barrier and the blood-brain barrier further enhancing inflammation at the gut, systemic and CNS levels.

In addition, a large amount of amyloids is secreted by the gut microbiota. Conflict of interest: None. Gut instincts: microbiota as a key regulator of brain development, ageing and neurodegeneration. J Physiol ; Quigley EMM. Microbiota-brain-gut axis and neurodegenerative iseases. Curr Neurol Neurosci Rep ; Frasca D, Blomberg BB. Inflammaging decreases adaptive and innate immune responses in mice and humans.

Biogerontology ; Curr Pharm Des ; Structural and functional features of central nervous system lymphatic vessels. Nature ; Indigenous bacteria from the gut microbiota regulate host serotonin biosynthesis. Cell ; Bhattacharjee S, Lukiw WJ. Front Cell Neurosci ; Reitz C, Mayeux R. Alzheimer disease: epidemiology, diagnostic criteria, risk factors and biomarkers. Biochem Pharmacol ; Eur J Med Chem ; Acta Neuropathol ; De Strooper B. Proteases and proteolysis in Alzheimer disease: a multi-factorial view on the disease process.

Physiol Rev ; Amyloid beta: structure, biology and structure-based therapeutic development.

Proteopathy - Wikipedia

Acta Pharmacol Sin ; Synapse formation and function is modulated by the amyloid precursor protein. J Neurosci ; Jucker M, Walker LC. Self-propagation of pathogenic protein aggregates in neurodegenerative diseases. Eisele YS. Brain Pathol ; Sci Transl Med ;ra Alzheimers Dement ; Allen HB. J Alzheimers Dis ; Am J Pathol ; Chalazonitis A, Rao M. Enteric nervous system manifestations of neurodegenerative disease.

Brain Res ; Pt B J Neurogastroenterol Motil ; The formation of Escherichia coli curli amyloid fibrils is mediated by prion-like peptide repeats.

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J Mol Biol ; The role of microbial amyloid in neurodegeneration. PLoS Pathog ;e J Alzheimers Dis Parkinsonism ; Friedland RP. Mechanisms of molecular mimicry involving the microbiota in neurodegeneration. Exposure to the functional bacterial amyloid protein curli enhances alpha-synuclein aggregation in aged Fischer rats and Caenorhabditis elegans. Sci Rep ; Protein fibrils in nature can enhance amyloid protein A amyloidosis in mice: cross-seeding as a disease mechanism.

Promiscuous cross-seeding between bacterial amyloids promotes interspecies biofilms. J Biol Chem ; LPS-induced neuroinflammatory effects do not recover with time. Each pathologically defined group showed variable sensitivity and specificity for the clinical diagnoses Supplementary Table 2. The largest group was hAD. Other groups had higher levels of clinicopathological correlation. Co-pathological tau was nearly universal, and was commonly observed in the hippocampal formation Braak I—II. D Distinct distributions of TDP pathology defined the primary TDP proteinopathies, but a common staging was possible for the remaining groups Josephs et al.

TDP was rare to non-existent in several groups and frequently had a limbic distribution. Thus, each neurodegenerative disease group can be divided into distinct subgroups: pure neurodegenerative disease with only primary pathology or neurodegenerative disease with single or multiple co-pathologies Fig. Tau was not included as a co-pathology for subsequent analysis because it was nearly universal in the cohort Table 2 and, if included as a co-pathology, would severely limit the number of cases in each pure neurodegenerative disease subgroup.

Table 2 Prevalence of co-pathologies by neurodegenerative disease group. Frequency of single and multiple neurodegenerative disease co-pathologies. Tau—represented by a black border—was ubiquitously present with the other co-pathologies, and only rarely negative in pure neurodegenerative disease cases.

Table 2 has the exact percentages for each co-pathology. Examination of age of onset, disease duration, and sex did not reveal an association with co-pathology versus pure neurodegenerative disease cases data not shown , but for several groups, age at death was a significantly increased in co-pathology cases. Other measures were not significantly different.

Other groups did not show significant differences.

Alzheimer's disease - plaques, tangles, causes, symptoms & pathology

There were variable clinocopathological correlations across groups Supplementary Table 2. By logistic regression, poor clinicopathological specificity did not associate with co-pathology in any group Supplementary Table 3. However, this was not the case in the Lewy body disease groups Fig. Table 4 Annual rate of change in clinical severity measures by neurodegenerative disease group. Co-pathology in Lewy body disease results in a faster cognitive decline. MMSE test scores estimated from a linear mixed-effect model were plotted over a year path.