Dement Neurocogn Disord.  2019 Jun;18(2):33-46. 10.12779/dnd.2019.18.2.33.

A Therapeutic Strategy for Alzheimer's Disease Focused on Immune-inflammatory Modulation

• Kim SH
• Noh MY
• Kim HJ
• Oh KW
• Park J
• Lee S
• Moon Y
• Kim YE
• Bae JS
• Jin HK
• K-ARPI

• KMID: 2451000
• DOI: http://doi.org/10.12779/dnd.2019.18.2.33

Abstract

Alzheimer's disease (AD), the most common form of dementia, has emerged as a major global public health challenge. However, the complexity of AD in its biological, genetic, and clinical aspects has hindered the development of effective therapeutic agents. Research plans that integrate new drug discoveries are urgently needed, including those based on novel and reliable biomarkers that reflect not only clinical phenotype, but also genetic and neuroimaging information. Therapeutic strategies such as stratification (i.e., subgrouping of patients having similar clinical characteristics or genetic background) and personalized medicine could be set as new directions for developing effective drugs for AD. In this review, we describe a therapeutic strategy that is based on immune-inflammation modulation for a subgroup of AD and related dementias, arguing that the use of stratification and personalized medicine is a promising way to achieve targeted medicine. The Korean AD Research Platform Initiative based on Immune-Inflammatory biomarkers (K-ARPI) has recently launched a strategy to develop novel biomarkers to identify a subpopulation of patients with AD and to develop new drug candidates for delaying the progression of AD by modulating toxic immune inflammatory response. Sphingosine kinase 1 (SphK1) and its metabolites, triggering receptor expressed on myeloid cells-2 (TREM2) related signals, and actin motility related proteins including Nck-associated protein 1 (Nap1) were selected as promising targets to modulate neuroinflammation. Their roles in stratification and personalized medicine will be discussed.

Keyword

Alzheimer's Disease; Inflammation; Personalized Medicine; Biomarkers

MeSH Terms

Actins
Alzheimer Disease*
Biomarkers
Dementia
Humans
Inflammation
Neuroimaging
Phenotype
Phosphotransferases
Precision Medicine
Public Health
Sphingosine
Actins
Biomarkers
Phosphotransferases
Sphingosine

Figure

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  Fig. 1 A comparison of drug development (A) and clinical trial paradigms (B) between the traditional model and future directions (modified from pharma 2020: the vision18). CIM: confidence in mechanism, CIS: confidence in safety.

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  Fig. 2 Characteristics of microglia showing two types of polarity (M1 and M2) and their characteristic cytokines and receptors. Possible candidates potentiating M2 polarity are summarized. M1: pro-inflammatory, M2: anti-inflammatory polarity, LPS: lipopolysaccharide, IFN: interferon, GM-CSF: granulocyte-macrophage colony-stimulating factor, TNF: tumor necrosis factor, IL: interleukin, SR: scavenger receptor, TGF: transforming growth factor, DMF: dimethylformamide, G-CSF-R: granulocyte colony-stimulating factor receptor, GSK-3: glycogen synthase kinase-3, HDAC: histone deacetylase, PPAR: peroxisome proliferator-activated receptor, AMPK: adenosine monophosphate-activated protein kinase, JAK/STAT: Janus kinase/signal transducers and activators of transcription.

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  Fig. 3 Generation of induced microglia like cells from peripheral blood mononuclear cells (A) and defected microglial phagocytosis in rapidly progressive AD compared to early AD and normal controls (B). AD: Alzheimer's disease, GM-CSF: granulocyte-macrophage colony-stimulating factor, IL-34: interleukin-34, I-MG: induced microglia, HC: healthy controls, AD (E): Alzheimer's disease (early), AD (R): Alzheimer's disease (rapidly).

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  Fig. 4 Conceptual fluid-like spectra of clinical phenotypes and functional characteristics of immune cells depending on the environment. M1: pro-inflammatory, M2: anti-inflammatory polarity, AD: Alzheimer's disease, SPM: specialized pro-resolving mediator, Th: T helper.

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  Fig. 5 Decision platform suggested by the K-ARPI. (A) Prescreening of AD patients for clustering with genetic information and clinical characteristics, imaging, biomarkers, and analysis. (B) Reclassification of prescreened clusters according to the algorithm using standardized biomarkers. (C) Schematic summary of the decision platform of the K-ARPI. K-ARPI: Korean AD Research Platform Initiative based on Immune-inflammatory biomarkers, AD: Alzheimer's disease, PET: positron emission tomography, CSF: cerebrospinal fluid.

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