Targeted TGF-ßR2 Knockdown in the Retrotrapezoid Nucleus Mitigates Respiratory Dysfunction and Cognitive Decline in a Mouse Model of Cerebral Amyloid Angiopathy with and without Stroke.

Introduction: Cerebral amyloid angiopathy (CAA) is characterized by the deposition of amyloid-beta peptides within cerebral blood vessels, leading to neurovascular complications. Ischemic strokes result from acute disruptions in cerebral blood flow, triggering metabolic disturbances and neurodegeneration. Both conditions often co-occur and are associated with respiratory dysfunctions. The retrotrapezoid nucleus (RTN), which is crucial for CO2 sensing and breathing regulation in the brainstem, may play a key role in breathing disorders seen in these conditions. This study aims to investigate the role of Transforming Growth Factor Beta (TGF-ß) signaling in the RTN on respiratory and cognitive functions in CAA, both with and without concurrent ischemic stroke. Methods: Adult male Tg-SwDI (CAA model) mice and C57BL/6 wild-type controls underwent stereotaxic injections of lentivirus targeting TGF-ß2R2 in the RTN. Stroke was induced by middle cerebral artery occlusion using a monofilament. Respiratory functions were assessed using whole-body plethysmography, while cognitive functions were evaluated through the Barnes Maze and Novel Object Recognition Test (NORT). Immunohistochemical analysis was conducted to measure TGF-ßR2 and GFAP expressions in the RTN. Results: CAA mice exhibited significant respiratory dysfunctions, including reduced respiratory rates and increased apnea frequency, as well as impaired cognitive performance. TGF-ßR2 knockdown in the RTN improved respiratory functions and cognitive outcomes in CAA mice. In CAA mice with concurrent stroke, TGF-ßR2 knockdown similarly enhanced respiratory and cognitive functions. Immunohistochemistry confirmed reduced TGF-ßR2 and GFAP expressions in the RTN following knockdown. Conclusions: Our findings demonstrate that increased TGF-ß signaling and gliosis in the RTN contribute to respiratory and cognitive dysfunctions in CAA and CAA with stroke. Targeting TGF-ßR2 signaling in the RTN offers a promising therapeutic strategy to mitigate these impairments. This study is the first to report a causal link between brainstem gliosis and both respiratory and cognitive dysfunctions in CAA and stroke models.

CCR2+ monocytes promote white matter injury and cognitive dysfunction after myocardial infarction.

Survivors of myocardial infarction are at increased risk for vascular dementia. Neuroinflammation has been implicated in the pathogenesis of vascular dementia, yet little is known about the cellular and molecular mediators of neuroinflammation after myocardial infarction. Using a mouse model of myocardial infarction coupled with flow cytometric analyses and immunohistochemistry, we discovered increased monocyte abundance in the brain after myocardial infarction, which was associated with increases in brain-resident perivascular macrophages and microglia. Myeloid cell recruitment and activation was also observed in post-mortem brains of humans that died after myocardial infarction. Spatial and single cell transcriptomic profiling of brain-resident myeloid cells after experimental myocardial infarction revealed increased expression of monocyte chemoattractant proteins. In parallel, myocardial infarction increased crosstalk between brain-resident myeloid cells and oligodendrocytes, leading to neuroinflammation, white matter injury, and cognitive dysfunction. Inhibition of monocyte recruitment preserved white matter integrity and cognitive function, linking monocytes to neurodegeneration after myocardial infarction. Together, these preclinical and clinical results demonstrate that monocyte infiltration into the brain after myocardial infarction initiate neuropathological events that lead to vascular dementia.

Miniature battery-free epidural cortical stimulators.

Miniaturized neuromodulation systems could improve the safety and reduce the invasiveness of bioelectronic neuromodulation. However, as implantable bioelectronic devices are made smaller, it becomes difficult to store enough power for long-term operation in batteries. Here, we present a battery-free epidural cortical stimulator that is only 9 millimeters in width yet can safely receive enough wireless power using magnetoelectric antennas to deliver 14.5-volt stimulation bursts, which enables it to stimulate cortical activity on-demand through the dura. The device has digitally programmable stimulation output and centimeter-scale alignment tolerances when powered by an external transmitter. We demonstrate that this device has enough power and reliability for real-world operation by showing acute motor cortex activation in human patients and reliable chronic motor cortex activation for 30 days in a porcine model. This platform opens the possibility of simple surgical procedures for precise neuromodulation.

Neurovascular Complications of Iatrogenic Fusarium solani Meningitis.

A multinational outbreak of nosocomial fusarium meningitis occurred among immunocompetent patients who had undergone surgery with epidural anesthesia in Mexico. The pathogen involved had a high predilection for the brain stem and vertebrobasilar arterial system and was associated with high mortality from vessel injury. Effective treatment options remain limited; in vitro susceptibility testing of the organism suggested that it is resistant to all currently approved antifungal medications in the United States. To highlight the severe complications associated with fusarium infection acquired in this manner, we report data, clinical courses, and outcomes from 13 patients in the outbreak who presented with symptoms after a median delay of 39 days.

Drivers of Chronic Pathology Following Ischemic Stroke: A Descriptive Review.

Stroke is the third leading cause of death and long-term disability in the world. Considered largely a disease of aging, its global economic and healthcare burden is expected to rise as more people survive into advanced age. With recent advances in acute stroke management, including the expansion of time windows for treatment with intravenous thrombolysis and mechanical thrombectomy, we are likely to see an increase in survival rates. It is therefore critically important to understand the complete pathophysiology of ischemic stroke, both in the acute and subacute stages and during the chronic phase in the months and years following an ischemic event. One of the most clinically relevant aspects of the chronic sequelae of stroke is its extended negative effect on cognition. Cognitive impairment may be related to the deterioration and dysfunctional reorganization of white matter seen at later timepoints after stroke, as well as ongoing progressive neurodegeneration. The vasculature of the brain also undergoes significant insult and remodeling following stroke, undergoing changes which may further contribute to chronic stroke pathology. While inflammation and the immune response are well established drivers of acute stroke pathology, the chronicity and functional role of innate and adaptive immune responses in the post-ischemic brain and in the peripheral environment remain largely uncharacterized. In this review, we summarize the current literature on post-stroke injury progression, its chronic pathological features, and the putative secondary injury mechanisms underlying the development of cognitive impairment and dementia. We present findings from clinical and experimental studies and discuss the long-term effects of ischemic stroke on both brain anatomy and functional outcome. Identifying mechanisms that occur months to years after injury could lead to treatment strategies in the chronic phase of stroke to help mitigate stroke-associated cognitive decline in patients.

Estradiol mediates colonic epithelial protection in aged mice after stroke and is associated with shifts in the gut microbiome.

The gut is a major source of bacteria and antigens that contribute to neuroinflammation after brain injury. Colonic epithelial cells (ECs) are responsible for secreting major cellular components of the innate defense system, including antimicrobial proteins (AMP) and mucins. These cells serve as a critical regulator of gut barrier function and maintain host-microbe homeostasis. In this study, we determined post-stroke host defense responses at the colonic epithelial surface in mice. We then tested if the enhancement of these epithelial protective mechanisms is beneficial in young and aged mice after stroke. AMPs were significantly increased in the colonic ECs of young males, but not in young females after experimental stroke. In contrast, mucin-related genes were enhanced in young females and contributed to mucus formation that maintains the distance between the host and gut bacteria. Bacterial community profiling was done using universal amplification of 16S rRNA gene sequences. The sex-specific colonic epithelial defense responses after stroke in young females were reversed with ovariectomy and led to a shift from a predominately mucin response to the enhanced AMP expression seen in males after stroke. Estradiol (E2) replacement prior to stroke in aged females increased mucin gene expression in the colonic ECs. Interestingly, we found that E2 treatment reduced stroke-associated neuronal hyperactivity in the insular cortex, a brain region that interacts with visceral organs such as the gut, in parallel to an increase in the composition of Lactobacillus and Bifidobacterium in the gut microbiota. This is the first study demonstrating sex differences in host defense mechanisms in the gut after brain injury.

Stabilizing histamine release in gut mast cells mitigates peripheral and central inflammation after stroke.

Stroke is the most common cause of long-term disability and places a high economic burden on the global healthcare system. Functional outcomes from stroke are largely determined by the extent of ischemic injury, however, there is growing recognition that systemic inflammatory responses also contribute to outcomes. Mast cells (MCs) rapidly respond to injury and release histamine (HA), a pro-inflammatory neurotransmitter that enhances inflammation. The gut serves as a major reservoir of HA. We hypothesized that cromolyn, a mast cell stabilizer that prevents the release of inflammatory mediators, would decrease peripheral and central inflammation, reduce MC trafficking to the brain, and improve stroke outcomes. We used the transient middle cerebral artery occlusion (MCAO) model of ischemic stroke in aged (18 mo) male mice to investigate the role of MC in neuroinflammation post-stroke. After MCAO we treated mice with 25 mg/kg body weight of cromolyn (MC stabilizer) by oral gavage. Cromolyn was administered at 3 h, 10 h, 24 h and every 24 h for 3 days post-stroke. Three control groups were used. One group underwent a sham surgery and was treated with cromolyn, one received sham surgery with PBS vehicle and the third underwent MCAO with PBS vehicle. Mice were euthanized at 24 h and 3 days post-stroke. Cromolyn administration significantly reduced MC numbers in the brain at both 24 h and 3 days post-stroke. Infarct volume was not significantly different between groups, however improved functional outcomes were seen at 3 days post-stroke in mice that received cromolyn. Treatment with cromolyn reduced plasma histamine and IL-6 levels in both the 24-h and 3-day cohorts. Gut MCs numbers were significantly reduced after cromolyn treatment at 24 h and 3 days after stroke. To determine if MC trafficking from the gut to the brain occurred after injury, GFP+MCs were adoptively transferred to c-kit-/- MC knock-out animals prior to MCAO. 24 h after stroke, elevated MC recruitment was seen in the ischemic brain. Preventing MC histamine release by cromolyn improved gut barrier integrity and an improvement in stroke-induced dysbiosis was seen with treatment. Our results show that preventing MC histamine release possesses prevents post-stroke neuroinflammation and improves neurological and functional outcomes.

CD13 facilitates immune cell migration and aggravates acute injury but promotes chronic post-stroke recovery.

INTRODUCTION: Acute stroke leads to the activation of myeloid cells. These cells express adhesion molecules and transmigrate to the brain, thereby aggravating injury. Chronically after stroke, repair processes, including angiogenesis, are activated and enhance post-stroke recovery. Activated myeloid cells express CD13, which facilitates their migration into the site of injury. However, angiogenic blood vessels which play a role in recovery also express CD13. Overall, the specific contribution of CD13 to acute and chronic stroke outcomes is unknown. METHODS: CD13 expression was estimated in both mice and humans after the ischemic stroke. Young (8-12 weeks) male wild-type and global CD13 knockout (KO) mice were used for this study. Mice underwent 60 min of middle cerebral artery occlusion (MCAO) followed by reperfusion. For acute studies, the mice were euthanized at either 24- or 72 h post-stroke. For chronic studies, the Y-maze, Barnes maze, and the open field were performed on day 7 and day 28 post-stroke. Mice were euthanized at day 30 post-stroke and the brains were collected for assessment of inflammation, white matter injury, tissue loss, and angiogenesis. Flow cytometry was performed on days 3 and 7 post-stroke to quantify infiltrated monocytes and neutrophils and CXCL12/CXCR4 signaling. RESULTS: Brain CD13 expression and infiltrated CD13+ monocytes and neutrophils increased acutely after the stroke. The brain CD13+lectin+ blood vessels increased on day 15 after the stroke. Similarly, an increase in the percentage area CD13 was observed in human stroke patients at the subacute time after stroke. Deletion of CD13 resulted in reduced infarct volume and improved neurological recovery after acute stroke. However, CD13KO mice had significantly worse memory deficits, amplified gliosis, and white matter damage compared to wild-type animals at chronic time points. CD13-deficient mice had an increased percentage of CXCL12+cells but a reduced percentage of CXCR4+cells and decreased angiogenesis at day 30 post-stroke. CONCLUSIONS: CD13 is involved in the trans-migration of monocytes and neutrophils after stroke, and acutely, led to decreased infarct size and improved behavioral outcomes. However, loss of CD13 led to reductions in post-stroke angiogenesis by reducing CXCL12/CXCR4 signaling.

Restoring a balanced pool of host-derived and microbiota-derived ligands of the aryl hydrocarbon receptor is beneficial after stroke.

Background: Stroke is a major cause of morbidity and mortality, and its incidence increases with age. While acute therapies for stroke are currently limited to intravenous thrombolytics and endovascular thrombectomy, recent studies have implicated an important role for the gut microbiome in post-stroke neuroinflammation. After stroke, several immuno-regulatory pathways, including the aryl hydrocarbon receptor (AHR) pathway, become activated. AHR is a master regulatory pathway that mediates neuroinflammation. Among various cell types, microglia (MG), as the resident immune cells of the brain, play a vital role in regulating post-stroke neuroinflammation and antigen presentation. Activation of AHR is dependent on a dynamic balance between host-derived and microbiota-derived ligands. While previous studies have shown that activation of MG AHR by host-derived ligands, such as kynurenine, is detrimental after stroke, the effects of post-stroke changes in microbiota-derived ligands of AHR, such as indoles, is unknown. Our study builds on the concept that differential activation of MG AHR by host-derived versus microbiome-derived metabolites affects outcomes after ischemic stroke. We examined the link between stroke-induced dysbiosis and loss of essential microbiota-derived AHR ligands. We hypothesize that restoring the balance between host-derived (kynurenine) and microbiota-derived (indoles) ligands of AHR is beneficial after stroke, offering a new potential avenue for therapeutic intervention in post-stroke neuroinflammation. Method: We performed immunohistochemical analysis of brain samples from stroke patients to assess MG AHR expression after stroke. We used metabolomics analysis of plasma samples from stroke and non-stroke control patients with matched comorbidities to determine the levels of indole-based AHR ligands after stroke. We performed transient middle cerebral artery occlusion (MCAO) in aged (18 months) wild-type (WT) and germ-free (GF) mice to investigate the effects of post-stroke treatment with microbiota-derived indoles on outcome. To generate our results, we employed a range of methodologies, including flow cytometry, metabolomics, and 16S microbiome sequencing. Results: We found that MG AHR expression is increased in human brain after stroke and after ex vivo oxygen-glucose deprivation and reperfusion (OGD/R). Microbiota-derived ligands of AHR are decreased in the human plasma at 24 hours after ischemic stroke. Kynurenine and indoles exhibited differential effects on aged WT MG survival after ex vivoOGD/R. We found that specific indole-based ligands of AHR (indole-3-propionic acid and indole-3-aldehyde) were absent in GF mice, thus their production depends on the presence of a functional gut microbiota. Additionally, a time-dependent decrease in the concentration of these indole-based AHR ligands occurred in the brain within the first 24 hours after stroke in aged WT mice. Post-stroke treatment of GF mice with a cocktail of microbiota-derived indole-based ligands of AHR regulated MG-mediated neuroinflammation and molecules involved in antigen presentation (increased CD80, MHC-II, and CD11b). Post-stroke treatment of aged WT mice with microbiota-derived indole-based ligands of AHR reduced both infarct volume and neurological deficits at 24 hours. Conclusion: Our novel findings provide compelling evidence that the restoration of a well-balanced pool of host-derived kynurenine-based and microbiota-derived indole-based ligands of AHR holds considerable therapeutic potential for the treatment of ischemic stroke.

Brain injury accelerates the onset of a reversible age-related microglial phenotype associated with inflammatory neurodegeneration.

Lipofuscin is an autofluorescent (AF) pigment formed by lipids and misfolded proteins, which accumulates in postmitotic cells with advanced age. Here, we immunophenotyped microglia in the brain of old C57BL/6 mice (>18 months old) and demonstrate that in comparison to young mice, one-third of old microglia are AF, characterized by profound changes in lipid and iron content, phagocytic activity, and oxidative stress. Pharmacological depletion of microglia in old mice eliminated the AF microglia following repopulation and reversed microglial dysfunction. Age-related neurological deficits and neurodegeneration after traumatic brain injury (TBI) were attenuated in old mice lacking AF microglia. Furthermore, increased phagocytic activity, lysosomal burden, and lipid accumulation in microglia persisted for up to 1 year after TBI, were modified by APOE4 genotype, and chronically driven by phagocyte-mediated oxidative stress. Thus, AF may reflect a pathological state in aging microglia associated with increased phagocytosis of neurons and myelin and inflammatory neurodegeneration that can be further accelerated by TBI.

The long noncoding RNA FEDORA is a cell type- and sex-specific regulator of depression.

Women suffer from depression at twice the rate of men, but the underlying molecular mechanisms are poorly understood. Here, we identify marked baseline sex differences in the expression of long noncoding RNAs (lncRNAs), a class of regulatory transcripts, in human postmortem brain tissue that are profoundly lost in depression. One such human lncRNA, RP11-298D21.1 (which we termed FEDORA), is enriched in oligodendrocytes and neurons and up-regulated in the prefrontal cortex (PFC) of depressed females only. We found that virally expressing FEDORA selectively either in neurons or in oligodendrocytes of PFC promoted depression-like behavioral abnormalities in female mice only, changes associated with cell type-specific regulation of synaptic properties, myelin thickness, and gene expression. We also found that blood FEDORA levels have diagnostic implications for depressed women and are associated with clinical response to ketamine. These findings demonstrate the important role played by lncRNAs, and FEDORA in particular, in shaping the sex-specific landscape of the brain and contributing to sex differences in depression.

Genetic impairment of succinate metabolism disrupts bioenergetic sensing in adrenal neuroendocrine cancer.

Metabolic dysfunction mutations can impair energy sensing and cause cancer. Loss of function of the mitochondrial tricarboxylic acid (TCA) cycle enzyme subunit succinate dehydrogenase B (SDHB) results in various forms of cancer typified by pheochromocytoma (PC). Here we delineate a signaling cascade where the loss of SDHB induces the Warburg effect, triggers dysregulation of [Ca2+]i, and aberrantly activates calpain and protein kinase Cdk5, through conversion of its cofactor from p35 to p25. Consequently, aberrant Cdk5 initiates a phospho-signaling cascade where GSK3 inhibition inactivates energy sensing by AMP kinase through dephosphorylation of the AMP kinase γ subunit, PRKAG2. Overexpression of p25-GFP in mouse adrenal chromaffin cells also elicits this phosphorylation signaling and causes PC. A potent Cdk5 inhibitor, MRT3-007, reverses this phospho-cascade, invoking a senescence-like phenotype. This therapeutic approach halted tumor progression in vivo. Thus, we reveal an important mechanistic feature of metabolic sensing and demonstrate that its dysregulation underlies tumor progression in PC and likely other cancers.

Integrated regulation of PKA by fast and slow neurotransmission in the nucleus accumbens controls plasticity and stress responses.

Cortical glutamate and midbrain dopamine neurotransmission converge to mediate striatum-dependent behaviors, while maladaptations in striatal circuitry contribute to mental disorders. However, the crosstalk between glutamate and dopamine signaling has not been entirely elucidated. Here we uncover a molecular mechanism by which glutamatergic and dopaminergic signaling integrate to regulate cAMP-dependent protein kinase (PKA) via phosphorylation of the PKA regulatory subunit, RIIß. Using a combination of biochemical, pharmacological, neurophysiological, and behavioral approaches, we find that glutamate-dependent reduction in cyclin-dependent kinase 5 (Cdk5)-dependent RIIß phosphorylation alters the PKA holoenzyme autoinhibitory state to increase PKA signaling in response to dopamine. Furthermore, we show that disruption of RIIß phosphorylation by Cdk5 enhances cortico-ventral striatal synaptic plasticity. In addition, we demonstrate that acute and chronic stress in rats inversely modulate RIIß phosphorylation and ventral striatal infusion of a small interfering peptide that selectively targets RIIß regulation by Cdk5 improves behavioral response to stress. We propose this new signaling mechanism integrating ventral striatal glutamate and dopamine neurotransmission is important to brain function, may contribute to neuropsychiatric conditions, and serves as a possible target for the development of novel therapeutics for stress-related disorders.

Cdk5 drives formation of heterogeneous pancreatic neuroendocrine tumors.

Pancreatic neuroendocrine tumors (PanNETs) are a heterogeneous population of neoplasms that arise from hormone-secreting islet cells of the pancreas and have increased markedly in incidence over the past four decades. Non-functional PanNETs, which occur more frequently than hormone-secreting tumors, are often not diagnosed until later stages of tumor development and have poorer prognoses. Development of successful therapeutics for PanNETs has been slow, partially due to a lack of diverse animal models for pre-clinical testing. Here, we report development of an inducible, conditional mouse model of PanNETs by using a bi-transgenic system for regulated expression of the aberrant activator of Cdk5, p25, specifically in ß-islet cells. This model produces a heterogeneous population of PanNETs that includes a subgroup of well-differentiated, non-functional tumors. Production of these tumors demonstrates the causative potential of aberrantly active Cdk5 for generation of PanNETs. Further, we show that human PanNETs express Cdk5 pathway components, are dependent on Cdk5 for growth, and share genetic and transcriptional overlap with the INS-p25OE model. The utility of this model is enhanced by the ability to form tumor-derived allografts. This new model of PanNETs will facilitate molecular delineation of Cdk5-dependent PanNETs and the development of new targeted therapeutics.

Neuropathological Effects of Chemotherapeutic Drugs.

Novel treatments, screening, and detection methods have prolonged the lives of numerous cancer patients worldwide. Unfortunately, existing and many promising new chemotherapeutics can cause deleterious, off-target side effects in normal tissue and organ systems. The central and peripheral nervous systems are widely recognized as frequent off-target effectors of anticancer drugs which can produce persistent neurological and neuropsychiatric symptoms collectively termed "chemobrain". Following chemotherapy, patients report several forms of cognitive impairment occurring acutely and sometimes persisting years after treatment. There are no effective treatments for cognitive decline induced by chemotherapeutics, and the underlying molecular mechanisms are poorly characterized and understood. In this study, we find that chronic treatment with two common chemotherapeutic agents, cisplatin and gemcitabine, impairs brain region-specific metabolism, hippocampus-dependent memory formation, and stress response behavior. This corresponds to reduced hippocampal synaptic excitability, altered neuronal signal transduction, and neuroinflammation. These findings underline that a better understanding of the basic pathological consequences of chemotherapy-induced cognitive impairment is the first step toward improving cancer treatment survivorship.

Machine learning reveals bilateral distribution of somatic L1 insertions in human neurons and glia.

Retrotransposons can cause somatic genome variation in the human nervous system, which is hypothesized to have relevance to brain development and neuropsychiatric disease. However, the detection of individual somatic mobile element insertions presents a difficult signal-to-noise problem. Using a machine-learning method (RetroSom) and deep whole-genome sequencing, we analyzed L1 and Alu retrotransposition in sorted neurons and glia from human brains. We characterized two brain-specific L1 insertions in neurons and glia from a donor with schizophrenia. There was anatomical distribution of the L1 insertions in neurons and glia across both hemispheres, indicating retrotransposition occurred during early embryogenesis. Both insertions were within the introns of genes (CNNM2 and FRMD4A) inside genomic loci associated with neuropsychiatric disorders. Proof-of-principle experiments revealed these L1 insertions significantly reduced gene expression. These results demonstrate that RetroSom has broad applications for studies of brain development and may provide insight into the possible pathological effects of somatic retrotransposition.

Hippocampal subfield transcriptome analysis in schizophrenia psychosis.

We have previously demonstrated functional and molecular changes in hippocampal subfields in individuals with schizophrenia (SZ) psychosis associated with hippocampal excitability. In this study, we use RNA-seq and assess global transcriptome changes in the hippocampal subfields, DG, CA3, and CA1 from individuals with SZ psychosis and controls to elucidate subfield-relevant molecular changes. We also examine changes in gene expression due to antipsychotic medication in the hippocampal subfields from our SZ ON- and OFF-antipsychotic medication cohort. We identify unique subfield-specific molecular profiles in schizophrenia postmortem samples compared with controls, implicating astrocytes in DG, immune mechanisms in CA3, and synaptic scaling in CA1. We show a unique pattern of subfield-specific effects by antipsychotic medication on gene expression levels with scant overlap of genes differentially expressed by SZ disease effect versus medication effect. These hippocampal subfield changes serve to confirm and extend our previous model of SZ and can explain the lack of full efficacy of conventional antipsychotic medication on SZ symptomatology. With future characterization using single-cell studies, the identified distinct molecular profiles of the DG, CA3, and CA1 in SZ psychosis may serve to identify further potential hippocampal-based therapeutic targets.

The effects of exercise therapy on the prognosis of patients with COVID-19: A protocol for systematic review.

BACKGROUND: Since the COVID-19 outbreak in 2020, more than 20 million people worldwide have been diagnosed with COVID-19, and all health care workers are looking for ways to improve the cure rate of the disease. As an important method of rehabilitation therapy, exercise therapy has been proved to improve the level of human function, promote the recovery of diseases, and improve the human immune ability. The main objective of this study was to provide reliable methods and credible evidence for exercise therapy to improve the prognosis of COVID-19 patients. METHODS AND ANALYSIS: The scheme was systematically reviewed in accordance with the preferred reporting items. We searched the following experimental databases: Cochrane Library, PubMed, EMBASE, Web of Science, China Biomedical Literature Database (CBM), China National Knowledge Infrastructure Database (CNKI), China Science and Wanfang Database. All trials using exercise therapy for rehabilitation of COVID-19 patients in the above database should be considered for inclusion. Relevant randomised controlled trials(RCTS), controlled before and after, interrupted time series and prospective analytic cohort studies regardless of publication date, language and geographic location, will be included. To summarize the therapeutic effect of exercise therapy on COVID-19 patients, high-quality literature was selected for data extraction and analysis. Two reviewers will independently screen titles, abstracts and full-text articles against inclusion criteria; perform data extraction and assess risk of bias in included studies. We will assess the certainty of the overall evidence using the Grading of Recommendations Assessment, Development and Evaluation approach and report findings accordingly. RESULTS: In this study, we hope to summarize effective exercise therapy that can improve the prognosis of COVID-19 patients and find strong evidence for it. CONCLUSIONS: The conclusions of this study will provide reliable evidence to determine whether exercise and exercise therapy can improve the prognosis of COVID-19 patients and guide future studies. PROSPERO REGISTRATION NUMBER: CRD42020209025.