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

Abstract

Alzheimer's disease (AD) is the most common age-related neurodegenerative disorder characterized by cognitive decline and by the presence of amyloid β plaques and neurofibrillary tangles in the brain. Despite recent advances in understanding its pathophysiological mechanisms, to date, there are no disease-modifying therapeutic options, to slow or halt the evolution of neurodegenerative processes in AD. Current pharmacological treatments only transiently mitigate the severity of symptoms, with modest or null overall improvement. Emerging evidence supports the concept that AD is affected by the impaired ability of the immune system to restrain the brain's pathology. Deep understanding of the relationship between the nervous and the immune system may provide a novel arena to develop effective and safe drugs for AD treatment. Considering the crucial role of inflammatory/immune pathways in AD, here we discuss the current status of the immuno-oncological, immunomodulatory and anti-TNF-α drugs which are being used in preclinical studies or in ongoing clinical trials by means of the drug-repositioning approach.

Keywords: clinical trial; disease-modifying therapy; drug repurposing; immune response; neuroinflammation.

FIGURE 1

Therapeutic potential of immuno-oncologicals in Alzheimer’s Disease. Immuno-oncological drugs could mark the beginning of a new era for treatment of AD-related neurodegeneration aimed to revitalize the body’s immune-mediated repair mechanisms by addressing multiple pathophysiological factors. As in cancer scenario, controlled trafficking of healing immunocytes to the injured brain could be considered as a mean to overcome immune escape mechanisms and to modify AD progression. Breaking regulatory T cell (Treg)-mediated systemic immune suppression and blocking inhibitory immune checkpoints, such as PD-1/PD-L1 with specific antibodies represents a crucial approach to enhance recruitment of pro-healing immunocytes to the brain parenchyma, culminating in attenuation of the disease-associated pathological features (e.g., dysfunction of lymphoid organs, increase of exhausted T cells, neuroinflammation, production of toxic proteins, neuronal damage and death). Moreover, release of proinflammatory factors that occurs in the brain during aging and AD, results in augmented expression of CD38 in glial cells, amplifying the neurodegenerative cycle. In turn, targeting CD38 with Daratumumab may represent a novel therapeutic approach for modulation of both AD-related neuroinflammation and Aβ production.

FIGURE 2

Snapshot of the main preclinical evidences for the implications of immunomodulatory drugs repositioned for Alzheimer’s disease. Summary of the most compelling preclinical evidences of the beneficial effects of immunomodulatory agents in the pathophysiological processes of Alzheimer’s disease, in view of possible future clinical development of immunomodulatory drug-based therapeutic strategies.

FIGURE 3

Targeting TNF-α signaling with TNF-α inhibitors in Alzheimer’s Disease pathology. Peripheral Tumor Necrosis Factor-α (TNF-α) enters the brain through the Blood-Brain Barrier (BBB) via transcytosis, upsetting its structural integrity and the permeability. TNF-α affects brain resident cells by binding Tumor Necrosis Factor Receptors (TNFRs), thus triggering activation of different intracellular cascades which redundantly lead to increased release of TNF-α. In addition, TNF-α leads to increased peripheral amyloid-β (Aβ) influx and generation of amyloid deposits into the brain parenchyma, which supplement the local amyloid burden, causing further production of TNF-α. Targeting membrane bound and/or soluble TNFα with small molecule inhibitors could represent a potential effective therapeutic approach acting at earliest steps of the AD-related neuroinflammatory vicious cycle, resulting in neuroprotection.