Towards retinoid therapy for Alzheimer's disease

K Shudo, H Fukasawa, M Nakagomi, N Yamagata, K Shudo, H Fukasawa, M Nakagomi, N Yamagata

Abstract

Alzheimer's disease(AD) is associated with a variety of pathophysiological features, including amyloid plaques, inflammation, immunological changes, cell death and regeneration processes, altered neurotransmission, and age-related changes. Retinoic acid receptors (RARs) and retinoids are relevant to all of these. Here we review the pathology, pharmacology, and biochemistry of AD in relation to RARs and retinoids, and we suggest that retinoids are candidate drugs for treatment of AD.

Figures

Fig. (1). Retinoid Dramatis Personae (Characters Involved…
Fig. (1). Retinoid Dramatis Personae (Characters Involved in Retinoid Therapy).
Neuron, dameged neuron, astrocyte (AS), microglia (MG), blood brain barrier (BBB), and other cellular members participate in the pathology of Alzheimer's disease. Retinol bound to retinol-binding protein (RBP) and TTR is transported from blood into brain. Retinol uptaked by brain cells is oxidised into retinal, then converterd into retinoic acid (RA). Cellular RA level is also regulated by cellular retinoic acid-binding proteins (CRABPs). By increase of α-secretase activity through ADAM10 induction and by other pathaways, retinoids decrease amyloid-β (Aβ) deposition from APP. Inflammatory response triggered by amyloid-β and other causes such as xenobiotics or chemicals is drived by inflammatory or proinflammatory cytokines and chemokines (IL-1b, IL-6, TNFa, MCP1 and others). Their production is suppressed by retinoids through RARs expressed in astrocyte and microglia. Cell death may be inhibited by the decrease of Aβ and suppression of inflammation. In regeneration from neural stem cells (NSC), retinoids have critical roles for their differentiation. Neurotransmission by Ach, DA and other molecules are affected by ChAT, dopamine D2 receptor (D2R), TrkB and t-PA which are transcriptionally regulated directly or indirectly by retinoid, influencing memory and learning. In addition, autoimmune pathways are regulated by T cells (Fig. 2 vide infra). In the scheme, + and - mean upregulation and down-regulation of the events or activities, by retinoids, respectively.
Fig. (2). Multiple actions of retinoid in…
Fig. (2). Multiple actions of retinoid in T cell differentiation.
Naive CD4-positive T cells differntiate into effector T cells (Th1, Th2, Th17) and regulatory T cells (Treg) in peripheral lymphoid tissues. Th1 cells whose differentiation is dependent on IL-12 and suppressed by retinoids mediate cellular immunity and physiologocal (and pathological) inflammation. Th2 cells mediate humoral immunity and allegy. Their differentiation is dependent on IL-4 and enhanced by retinods, but suppressed by coexistence of retinoids and TGFβ. IL-17-producing Th17 cells mediate pathological chronic inflammation or autoimmune inflammation. Th17 diffrentiation is induced by coexistence of IL-6 and TGFβ, and maintained by IL-23. By contrast, differentiation of Treg cells is induced by TGFβ alone and suppressed by IL-6. Treg cells suppress effector T cell activities and and thereby maintain immune system homeostasis and self-tolerance. Retinoids strongly enhance TGFβ-induced Treg diffenentiation and suppress Th17 differentiation even in the presence of IL-6.

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