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Review
. 2024 Jan 5:17:1256100.
doi: 10.3389/fncel.2023.1256100. eCollection 2023.

Alzheimer's disease and microorganisms: the non-coding RNAs crosstalk

Hanieh Mohammadi-Pilehdarboni  1   2 , Mohammad Shenagari  2   3 , Farahnaz Joukar  2 , Hamed Naziri  4 , Fariborz Mansour-Ghanaei  2
Affiliations
Review

Alzheimer's disease and microorganisms: the non-coding RNAs crosstalk

Hanieh Mohammadi-Pilehdarboni et al. Front Cell Neurosci. .

Abstract

Alzheimer's disease (AD) is a complex, multifactorial disorder, influenced by a multitude of variables ranging from genetic factors, age, and head injuries to vascular diseases, infections, and various other environmental and demographic determinants. Among the environmental factors, the role of the microbiome in the genesis of neurodegenerative disorders (NDs) is gaining increased recognition. This paradigm shift is substantiated by an extensive body of scientific literature, which underscores the significant contributions of microorganisms, encompassing viruses and gut-derived bacteria, to the pathogenesis of AD. The mechanism by which microbial infection exerts its influence on AD hinges primarily on inflammation. Neuroinflammation, activated in response to microbial infections, acts as a defense mechanism for the brain but can inadvertently lead to unexpected neuropathological perturbations, ultimately contributing to NDs. Given the ongoing uncertainty surrounding the genetic factors underpinning ND, comprehensive investigations into environmental factors, particularly the microbiome and viral agents, are imperative. Recent advances in neuroscientific research have unveiled the pivotal role of non-coding RNAs (ncRNAs) in orchestrating various pathways integral to neurodegenerative pathologies. While the upstream regulators governing the pathological manifestations of microorganisms remain elusive, an in-depth exploration of the nuanced role of ncRNAs holds promise for the development of prospective therapeutic interventions. This review aims to elucidate the pivotal role of ncRNAs as master modulators in the realm of neurodegenerative conditions, with a specific focus on Alzheimer's disease.

Keywords: Alzheimer’s disease; gut microbiome; gut–brain axis; neurodegenerative disorders; non-coding RNAs; viral disease.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Molecular mechanisms underlying Alzheimer’s disease pathology. At the molecular level within neurons, Alzheimer’s disease (AD) is characterized by the self-aggregation of amyloid-β peptides into plaques and hyperphosphorylation of the tau protein. These pathological events can trigger microglial activation, leading to an increase in blood–brain barrier (BBB) permeability and subsequent neuroinflammation, which results in neural impairments. Clinically, individuals with AD often exhibit a range of symptoms such as deficits in intelligence and judgment behavior, speech difficulties, and memory loss. Brain magnetic resonance imaging (MRI) reveals significant structural changes, including cerebral cortex shrinkage and ventricular enlargement, highlighting the structural alterations associated with the progression of AD.
Figure 2
Figure 2
Classification of non-coding RNAs (ncRNAs). In a general categorization, non-coding RNAs (ncRNAs) can be systematically classified into two fundamental groups: circular and linear RNAs. Linear RNAs, further delineated based on their functional roles and expression patterns, segregate into two categories: housekeeping and regulatory elements. The housekeeping group consists of elements that are typically expressed at a constant level, including transfer RNA (tRNA), ribosomal RNA (rRNA), small nuclear RNA (snRNA), and small nucleolar RNA (snoRNA). In contrast, regulatory elements are subdivided into short and long ncRNAs based on their respective lengths. This classification provides a foundational framework for understanding the diverse landscape of ncRNAs and their pivotal roles in cellular processes and disease pathogenesis.
Figure 3
Figure 3
The Impact of the Lactobacillus-mediated regulation of Sirt1-AS, a long non-coding RNA, on human brain health. Lactobacillus-produced lactate plays a crucial role in orchestrating the activation of Sirt1-AS, a long non-coding RNA, effectively outcompeting miRNA-34a to protect the Sirt-1 mRNA transcript. This transcript encodes the histone deacetylase enzyme, which is known for its pivotal role in enhancing synaptic plasticity. Furthermore, this enzyme has the ability to effectively reduce neuroinflammation by inhibiting NF-KB signaling. Given its reliance on nicotinamide adenine dinucleotide (NAD+) and predominant localization within mitochondria, any disruption in mitochondrial function may exacerbate neurodegenerative pathologies. The figure underscores the intricate interplay between microbiota-derived molecules, RNA regulation, and neuroprotective mechanisms, offering promising therapeutic prospects.
Figure 4
Figure 4
The impact of HIV on Alzheimer’s amyloidogenic pathway. This figure provides an overview of how HIV infection can influence Alzheimer’s disease (AD) mechanisms, particularly the amyloidogenic pathway. BACE1-AS acts as a competing endogenous RNA (ceRNA), sequestering miRNA-485-5p, which in turn, enhances BACE1 mRNA expression, ultimately contributing to Aβ generation in AD. Studies on CNS lentiviruses have revealed their ability to induce the expression of miRNA-31, which reduces Aβ deposition in brain regions such as the subiculum and hippocampus, and this suggests a potential role for non-coding RNAs (ncRNAs) in the pathology of AD. However, due to the intricate and sometimes contradictory effects of diverse lentiviruses on AD, further comprehensive investigations remain essential to fully understand this complex interaction.
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