Repositioning of Immunomodulators: A Ray of Hope for Alzheimer’s Disease?

Munafò, Antonio; Burgaletto, Chiara; Benedetto, Giulia Di; Mauro, M. Di; Mauro, Rosaria Di; Bernardini, Renato; Cantarella, Giuseppina

doi:10.3389/fnins.2020.614643

Cited by 19 publications

(15 citation statements)

References 134 publications

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“…Thus, we need new treatments targeting other pathomechanisms of the disease such as the neuroinflammation. 265 , 266 …”

Section: What About Interventions?mentioning

confidence: 99%

“…Some immunomodulating agents may also be considered for AD treatment. 266 Copaxone used in multiple sclerosis to boost the T cell immune response could modulate the microglia response. 355 Rapamycin, an mTOR inhibitor used as anti-aging drug, could be considered as an immunomodulatory drug in case of AD as preclinical data showed that it can maintain BBB integrity and decrease Aβ pathology.…”

Section: Reinforcement Of the Antimicrobial Defense By Stimulating The Immune System (Immunomodulation)mentioning

confidence: 99%

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Targeting Impaired Antimicrobial Immunity in the Brain for the Treatment of Alzheimer’s Disease

Fülöp¹,

Tripathi²,

Rodrigues³

et al. 2021

NDT

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Alzheimer’s disease (AD) is the most common form of dementia and aging is the most common risk factor for developing the disease. The etiology of AD is not known but AD may be considered as a clinical syndrome with multiple causal pathways contributing to it. The amyloid cascade hypothesis, claiming that excess production or reduced clearance of amyloid-beta (Aβ) and its aggregation into amyloid plaques, was accepted for a long time as the main cause of AD. However, many studies showed that Aβ is a frequent consequence of many challenges/pathologic processes occurring in the brain for decades. A key factor, sustained by experimental data, is that low-grade infection leading to production and deposition of Aβ, which has antimicrobial activity, precedes the development of clinically apparent AD. This infection is chronic, low grade, largely clinically silent for decades because of a nearly efficient antimicrobial immune response in the brain. A chronic inflammatory state is induced that results in neurodegeneration. Interventions that appear to prevent, retard or mitigate the development of AD also appear to modify the disease. In this review, we conceptualize further that the changes in the brain antimicrobial immune response during aging and especially in AD sufferers serve as a foundation that could lead to improved treatment strategies for preventing or decreasing the progression of AD in a disease-modifying treatment.

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“…Thus, we need new treatments targeting other pathomechanisms of the disease such as the neuroinflammation. 265 , 266 …”

Section: What About Interventions?mentioning

confidence: 99%

Section: Reinforcement Of the Antimicrobial Defense By Stimulating The Immune System (Immunomodulation)mentioning

confidence: 99%

Targeting Impaired Antimicrobial Immunity in the Brain for the Treatment of Alzheimer’s Disease

Fülöp¹,

Tripathi²,

Rodrigues³

et al. 2021

NDT

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“…Recent evidence suggests that changes in peripheral and central adaptive immunity occur in AD patients. Nevertheless, anti-inflammatory drugs have produced disappointing results in AD treatment [ 26 ].…”

Section: Introductionmentioning

confidence: 99%

Bladder Cancer Immunotherapy by BCG Is Associated with a Significantly Reduced Risk of Alzheimer’s Disease and Parkinson’s Disease

et al. 2021

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Bacillus Calmette–Guerin (BCG) is a live attenuated form of Mycobacterium bovis that was developed 100 years ago as a vaccine against tuberculosis (TB) and has been used ever since to vaccinate children globally. It has also been used as the first-line treatment in patients with nonmuscle invasive bladder cancer (NMIBC), through repeated intravesical applications. Numerous studies have shown that BCG induces off-target immune effects in various pathologies. Accumulating data argue for the critical role of the immune system in the course of neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). In this study, we tested whether repeated exposure to BCG during the treatment of NMIBC is associated with the risk of developing AD and PD. We presented a multi-center retrospective cohort study with patient data collected between 2000 and 2019 that included 12,185 bladder cancer (BC) patients, of which 2301 BCG-treated patients met all inclusion criteria, with a follow-up of 3.5 to 7 years. We considered the diagnosis date of AD and nonvascular dementia cases for BC patients. The BC patients were partitioned into those who underwent a transurethral resection of the bladder tumor followed by BCG therapy, and a disjoint group that had not received such treatment. By applying Cox proportional hazards (PH) regression and competing for risk analyses, we found that BCG treatment was associated with a significantly reduced risk of developing AD, especially in the population aged 75 years or older. The older population (≥75 years, 1578 BCG treated, and 5147 controls) showed a hazard ratio (HR) of 0.726 (95% CI: 0.529–0.996; p-value = 0.0473). While in a hospital-based cohort, BCG treatment resulted in an HR of 0.416 (95% CI: 0.203–0.853; p-value = 0.017), indicating a 58% lower risk of developing AD. The risk of developing PD showed the same trend with a 28% reduction in BCG-treated patients, while no BCG beneficial effect was observed for other age-related events such as Type 2 diabetes (T2D) and stroke. We attributed BCG’s beneficial effect on neurodegenerative diseases to a possible activation of long-term nonspecific immune effects. We proposed a prospective study in elderly people for testing intradermic BCG inoculation as a potential protective agent against AD and PD.

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“…In preclinical studies, dimethyl fumarate, an immunomodulatory compound used to treat multiple sclerosis, seems to have neuroprotective effects, reducing neuroinflammation and improving cognitive performance in rats infused with streptozotocin ( Majkutewicz et al, 2016 ). Currently, several immune-oncological and anti-TNF-α compounds are under preclinical and clinical investigation as neuroprotectants in AD, as elegantly reviewed elsewhere in this issue ( Munafò et al, 2020 ). Of note, recent preclinical data have shown that a checkpoint inhibitor against the programmed death-1 (PD-1) protein, clinically used in cancer immunotherapy, resulted in improved clearance of cerebral Aβ plaques and cognitive performance in an animal model of AD ( Baruch et al, 2016 ).…”

Section: Neuroinflammation In Neurological Disordersmentioning

confidence: 99%

Repurposing Immunomodulatory Imide Drugs (IMiDs) in Neuropsychiatric and Neurodegenerative Disorders

et al. 2021

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Neuroinflammation represents a common trait in the pathology and progression of the major psychiatric and neurodegenerative disorders. Neuropsychiatric disorders have emerged as a global crisis, affecting 1 in 4 people, while neurological disorders are the second leading cause of death in the elderly population worldwide (WHO, 2001; GBD 2016 Neurology Collaborators, 2019). However, there remains an immense deficit in availability of effective drug treatments for most neurological disorders. In fact, for disorders such as depression, placebos and behavioral therapies have equal effectiveness as antidepressants. For neurodegenerative diseases such as Parkinson’s disease and Alzheimer’s disease, drugs that can prevent, slow, or cure the disease have yet to be found. Several non-traditional avenues of drug target identification have emerged with ongoing neurological disease research to meet the need for novel and efficacious treatments. Of these novel avenues is that of neuroinflammation, which has been found to be involved in the progression and pathology of many of the leading neurological disorders. Neuroinflammation is characterized by glial inflammatory factors in certain stages of neurological disorders. Although the meta-analyses have provided evidence of genetic/proteomic upregulation of inflammatory factors in certain stages of neurological disorders. Although the mechanisms underpinning the connections between neuroinflammation and neurological disorders are unclear, and meta-analysis results have shown high sensitivity to factors such as disorder severity and sample type, there is significant evidence of neuroinflammation associations across neurological disorders. In this review, we summarize the role of neuroinflammation in psychiatric disorders such as major depressive disorder, generalized anxiety disorder, post-traumatic stress disorder, and bipolar disorder, as well as in neurodegenerative disorders, such as Parkinson’s disease and Alzheimer’s disease, and introduce current research on the potential of immunomodulatory imide drugs (IMiDs) as a new treatment strategy for these disorders.

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Repositioning of Immunomodulators: A Ray of Hope for Alzheimer’s Disease?

Cited by 19 publications

References 134 publications

Targeting Impaired Antimicrobial Immunity in the Brain for the Treatment of Alzheimer’s Disease

Targeting Impaired Antimicrobial Immunity in the Brain for the Treatment of Alzheimer’s Disease

Bladder Cancer Immunotherapy by BCG Is Associated with a Significantly Reduced Risk of Alzheimer’s Disease and Parkinson’s Disease

Repurposing Immunomodulatory Imide Drugs (IMiDs) in Neuropsychiatric and Neurodegenerative Disorders

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