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Microbiota Alterations in Alzheimer's Disease: Involvement of The Neurotoxicity Research (2019) 36:424–436 https://doi.org/10.1007/s12640-019-00057-3 REVIEW ARTICLE Microbiota Alterations in Alzheimer’s Disease: Involvement of the Kynurenine Pathway and Inflammation Michelle L. Garcez1 & Kelly R. Jacobs1 & Gilles J. Guillemin1 Received: 13 December 2018 /Revised: 30 April 2019 /Accepted: 2 May 2019 /Published online: 14 May 2019 # Springer Science+Business Media, LLC, part of Springer Nature 2019 Abstract Alzheimer’s disease (AD) is a neurodegenerative disease considered the major cause of dementia in the elderly. The main pathophysiological features of the disease are neuronal loss (mainly cholinergic neurons), glutamatergic excitotoxicity, extracel- lular accumulation of amyloid beta, and intracellular neurofibrillary tangles. However, other pathophysiological features of the disease have emerged including neuroinflammation and dysregulation of the kynurenine pathway (KP). The intestinal microbiota is a large and diverse collection of microorganisms that play a crucial role in regulating host health. Recently, studies have highlighted that changes in intestinal microbiota contribute to brain dysfunction in various neurological diseases including AD. Studies suggest that microbiota compositions are altered in AD patients and animal models and that these changes may increase intestinal permeability and induce inflammation. Considering that microbiota can modulate the kynurenine pathway and in turn neuroinflammation, the gut microbiome may be a valuable target for the development of new disease-modifying therapies. The present review aims to link the interactions between AD, microbiota, and the KP. Keywords Alzheimer’sdisease . Microbiota . Probiotics . Inflammation . Kynurenine pathway Alzheimer’sDisease However, in sporadic late-onset AD (LOAD), which accounts for over 90% of AD cases, apolipoprotein E (APOE) gene poly- Alzheimer’s disease (AD) is a chronic neurodegenerative dis- morphisms are the only known genetic risk factor consistently ease that causes progressive loss of brain functions resulting in identified (Yu et al. 2014). Several other genes have been iden- memory, spatial orientation, language, and behavioral deficits tified following genome-wide association studies including that leave patients dependent on caregivers (Howard et al. genes involved in the inflammatory response such as comple- 2015; Prischmann 2016; Vickers et al. 2016). ment receptor 1 (CR1), CD33, membrane-spanning 4A (MS4A), clusterin (CLU), ATP-binding cassette sub-family A member 7 Alzheimer’sDiseaseEtiology (ABCA7), and ephrin receptor A1 (Lambert et al. 2013). Genes related to microglia function such as inositol polyphosphate-5- The etiology of AD has not been fully elucidated, but multiple phosphatase D (INPP5D) and genes related to endocytosis in- environmental and genetic factors appear to be involved. Several cluding phosphatidylinositol-binding clathrin assembly protein gene mutations have been implicated in the development of fa- (PICALM), triggering receptor expressed on myeloid cells 1 milial AD including amyloid precursor protein (APP), presenilin and 2 (TREM1, TREM2), and sortilin related receptor 1 1(PSEN1),andpresenilin2(PSEN2) (Lanoiselee et al. 2017). (SORL1) have also been reported (Lambert et al. 2013; Ridge et al. 2016). Environmental factors related to the development of AD include gender, low levels of education, depression, diabetes, * Gilles J. Guillemin and low cognitive activity (Durazzo et al. 2014; Schipper [email protected] 2011). However, aging is the main risk factor, with prevalence doubling every 5 years from the age of 65 (Savva et al. 2009). 1 Neuroinflammation Group, Department of Biomedical Sciences, The prevalence of the disease is estimated as 0.7% in individ- Faculty of Medicine and Health Sciences, Macquarie University, uals among 60–64-year-olds and increases to 5.6% among Sydney, NSW 2109, Australia Neurotox Res (2019) 36:424–436 425 70–79-year-olds, reaching approximately 38.6% in people Intestinal Microbiota aged 90 years or older (Dubois et al. 2016). The gut microbiota–brain axis comprises many fundamental el- ements including the CNS, neuroendocrine and neuroimmune Pathological Features of Alzheimer’sDisease systems, autonomic nervous system, enteric nervous system (ENS), and the intestinal microbiome (Moloney et al. 2014). A Neuronal loss, amyloid beta (Aβ) accumulation, and neurofi- triad of neural, hormonal, and immunological lines of communi- brillary tangles (NFTs) are the histopathological hallmarks of cation combines to allow the brain to influence the motor, sen- the AD (Sery et al. 2013). Hyperphosphorylated tau protein is sory, autonomic, and secretory functions of the gastrointestinal the major component of NFTs and accumulates in the tract (Kennedy et al. 2014). These same connections allow the somatodendritic compartment of neurons leading to a loss of gastrointestinal tract to affect brain function (Mayer 2011;Van stability and function of the neuronal cytoskeleton (Avila et al. der Leek et al. 2017) and although the reciprocal communication 2010; Hernandez et al. 2013; Iqbal et al. 2009). Aβ peptide between ENS and the CNS is well described, the role of the with 40 or 42 amino acids (Aβ40 and Aβ42) accumulates and intestinal microbiota within this system remains unclear. form extracellular senile plaques following abnormal process- Bacterial cells within the human body exceed human cells 10 ing of the amyloid precursor protein (APP) (Buoso et al. 2010; to 1, and their total gene count exceeds that of the host more than Serrano-Pozo et al. 2011). These hallmarks are commonly 100-fold (Backhed et al. 2005; Ley et al. 2006). In addition to the observed in brain regions responsible for cognitive function production of neurotransmitters such as serotonin, dopamine, such as the cerebral cortex, hippocampus, entorhinal cortex, noradrenaline, and GABA (Clarke et al. 2014)resultsinnumer- and ventral striatum (Selkoe 2008). ous biological processes that would otherwise be unavailable to Glutamatergic dysfunction occurs early in AD progression the host. For example, the production of indole following the and is evident before the decline in cognitive abilities (Rudy metabolism of tryptophan (Trp) by tryptophanase, an enzyme et al. 2015; Scott et al. 2011). Glutamate is a key central not present in eukaryotic cells (Scherzer et al. 2009). Impacts nervous system (CNS) neurotransmitter and contributes to of tryptophan-derived indoles are varied and include changes to learning and memory formation through long-term potentia- oxidative stress, intestinal inflammation, hormone secretions, and tion (LTP) (Bliss and Collingridge 1993). However, at high the mucosal barrier (Lee et al. 2015) as discussed in the concentrations extracellular glutamate can lead to cell death BMicrobiota and Tryptophan Metabolism^ section. through the excessive activation of the N-methyl-D-aspartate During human development different intrinsic and extrinsic (NMDA) receptor, a process known as glutamatergic factors can affect intestinal microbiota and it has been hypoth- excitotoxicity (Wang and Qin 2010). Abnormal activation of esized that the consolidation of Ba healthy/unhealthy these signaling pathways may lead to synaptic dysfunction, microbiota^ occurs between birth and early childhood and activation of pro-apoptotic caspases, and activation of the may contribute to the emergence of chronic diseases later in calcium-dependent pathway of calpain causing neuronal loss life (Junges et al. 2018). (Crews and Masliah 2010;Morales-Cruzetal.2014). Neuroinflammation is another critical pathophysiological Microbial Metabolites and the Immune System feature observed in the AD. Activation of microglia and as- trocytes leads to the production of inflammatory mediators Microbial colonization plays an important role in the develop- such as cytokines, chemokines, and reactive oxygen species ment of the immune system. For example, it has been shown that (ROS) (Tan et al. 2013). Indeed, recent studies have demon- intestinal microbiota influences maturation and microglial func- strated that the Aβ peptide can activate microglial pattern tion. In contrast to conventionally colonized controls, germ-free recognition receptors (PRRs) (Bachstetter et al. 2011;Lin mice show an increase in the number of immature microglia in et al. 2013). This neuroinflammation caused by the Aβ1–42 the gray and white matter of the cortex, corpus callosum, hippo- peptide initially occurs following activation of toll-like recep- campus, olfactory bulb, and cerebellum (Erny et al. 2015). tors 2, 4, and 6 (TLR) (Liu et al. 2012;Udanetal.2008)andin Furthermore, microbe-associated molecular pattern turn induces the activation of the immune system and the (MAMPs; e.g., lipopolysaccharides (LPS), bacterial lipopro- production of inflammatory mediators (Cuello et al. 2010; teins (BLP), flagellin and CpG DNA) activates several cells of Lin et al. 2013). An increase in pro-inflammatory cytokines the immune system including macrophages, neutrophils, and was observed in serum, brain, and cerebrospinal fluid (CSF) dendritic cells. Once activated these cells produce pro- of AD patients (Dursun et al. 2015;Jacketal.2013;Zhang inflammatory cytokines such as IL-1β,TNF-α, and IL-6, et al. 2013). Furthermore, several studies highlight correla- which target the brain through the blood-brain barrier (BBB) tions between the level of pro-inflammatory cytokines and (Sampson and Mazmanian 2015) and are involved in the de- cognitive
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