The clinical manifestation of COVID-19, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), in the respiratory system of humans is widely recognized. There is increasing evidence suggesting that SARS-CoV-2 possesses the capability to invade the gastrointestinal (GI) system, leading to the manifestation of symptoms such as vomiting, diarrhea, abdominal pain, and GI lesions. These symptoms subsequently contribute to the development of gastroenteritis and inflammatory bowel disease (IBD). Nevertheless, the pathophysiological mechanisms linking these GI symptoms to SARS-CoV-2 infection remain unelucidated. During infection, SARS-CoV-2 binds to angiotensin-converting enzyme 2 and other host proteases in the GI tract during the infection, possibly causing GI symptoms by damaging the intestinal barrier and stimulating inflammatory factor production, respectively. The symptoms of COVID-19-induced GI infection and IBD include intestinal inflammation, mucosal hyperpermeability, bacterial overgrowth, dysbiosis, and changes in blood and fecal metabolomics. Deciphering the pathogenesis of COVID-19 and understanding its exacerbation may provide insights into disease prognosis and pave the way for the discovery of potential novel targets for disease prevention or treatment. Besides the usual transmission routes, SARS-CoV-2 can also be transmitted via the feces of an infected person. Hence, it is crucial to implement preventive and control measures in order to mitigate the fecal-to-oral transmission of SARS-CoV-2. Within this context, the identification and diagnosis of GI tract symptoms during these infections assume significance as they facilitate early detection of the disease and the development of targeted therapeutics. The present review discusses the receptors, pathogenesis, and transmission of SARS-CoV-2, with a particular focus on the induction of gut immune responses, the influence of gut microbes, and potential therapeutic targets against COVID-19-induced GI infection and IBD.

Many neurodegenerative diseases, such as Alzheimer’s disease (AD) and frontotemporal dementia with Parkinsonism linked to chromosome 17, are characterized by tau pathology. Numerous motor proteins, many of which are involved in synaptic transmission, mediate transport in neurons. Dysfunction in motor protein-mediated neuronal transport mechanisms occurs in several neurodegenerative disorders but remains understudied in AD. Kinesins are the most important molecular motor proteins required for microtubule-dependent transport in neurons, and kinesin-1 is crucial for neuronal transport among all kinesins. Although kinesin-1 is required for normal neuronal functions, the dysfunction of these motor domains leading to neurodegenerative diseases is not fully understood. Here, we reported that the kinesin-I heavy chain (KIF5B), a key molecular motor protein, is involved in tau homeostasis in AD cells and animal models. We found that the levels of KIF5B in P301S tau mice are high. We also found that the knockdown and knockout (KO) of KIFf5B significantly decreased the tau stability, and overexpression of KIF5B in KIF5B-KO cells significantly increased the expression of phosphorylated and total tau levels. This suggested that KIF5B might prevent tau accumulation. By conducting experiments on P301S tau mice, we showed that partially reducing KIF5B levels can reduce hyperphosphorylation of the human tau protein, formation of insoluble aggregates, and memory impairment. Collectively, our results suggested that decreasing KIF5B levels is sufficient to prevent and/or slow down abnormal tau behavior of AD and other tauopathies.

Alzheimer’s disease (AD) is marked by the gradual and age-related deterioration of nerve cells in the central nervous system. The histopathological features observed in the brain affected by AD are the aberrant buildup of extracellular and intracellular amyloid-β and the formation of neurofibrillary tangles consisting of hyperphosphorylated tau protein. Axonal transport is a fundamental process for cargo movement along axons and relies on molecular motors like kinesins and dyneins. Kinesin’s responsibility for transporting crucial cargo within neurons implicates its dysfunction in the impaired axonal transport observed in AD. Impaired axonal transport and dysfunction of molecular motor proteins, along with dysregulated signaling pathways, contribute significantly to synaptic impairment and cognitive decline in AD. Dysregulation in tau, a microtubule-associated protein, emerges as a central player, destabilizing microtubules and disrupting the transport of kinesin-1. Kinesin-1 superfamily members, including kinesin family members 5A, 5B, and 5C, and the kinesin light chain, are intricately linked to AD pathology. However, inconsistencies in the abundance of kinesin family members in AD patients underline the necessity for further exploration into the mechanistic impact of these motor proteins on neurodegeneration and axonal transport disruptions across a spectrum of neurological conditions. This review underscores the significance of kinesin-1’s anterograde transport in AD. It emphasizes the need for investigations into the underlying mechanisms of the impact of motor protein across various neurological conditions. Despite current limitations in scientific literature, our study advocates for targeting kinesin and autophagy dysfunctions as promising avenues for novel therapeutic interventions and diagnostics in AD.

Natively unfolded tau has a low propensity to form aggregates, but in tauopathies, such as Alzheimer’s disease (AD), tau aggregates into paired helical filaments (PHFs) and neurofibrillary tangles (NFTs). Multiple intracellular transport pathways utilize kinesin-1, a plus-end-directed microtubule-based motor. Kinesin-1 is crucial in various neurodegenerative diseases as it transports multiple cargoes along the microtubules (MT). Kinesin-1 proteins cannot progress along MTs due to an accumulation of tau on their surfaces. Although kinesin-1-mediated neuronal transport dysfunction is well-documented in other neurodegenerative diseases, its role in AD has received less attention. Very recently, we have shown that knocking down and knocking out of kinesin-1 heavy chain (KIF5B KO) expression significantly reduced the level and stability of tau in cells and tau transgenic mice, respectively. Here, we report that tau interacts with the motor domain of KIF5B in vivo and in vitro, possibly through its microtubule-binding repeat domain. This interaction leads to the inhibition of the ATPase activity of the motor domain. In addition, the KIF5B KO results in autophagy initiation, which subsequently assists in tau degradation. The mechanisms behind KIF5B KO-mediated tau degradation seem to involve its interaction with tau, promoting the trafficking of tau through retrograde transport into autophagosomes for subsequent lysosomal degradation of tau. Our results suggest how KIF5B removal facilitates the movement of autophagosomes toward lysosomes for efficient tau degradation. This mechanism can be enabled through the downregulation of kinesin-1 or the disruption of the association between kinesin-1 and tau, particularly in cases when neurons perceive disturbances in intercellular axonal transport.

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