Abstract
Retinoic acid has been previously proposed in the treatment of Alzheimer’s disease (AD). Here, five transgenic mouse models expressing AD and frontotemporal dementia risk genes (i.e., PLB2APP, PLB2TAU, PLB1Double, PLB1Triple, and PLB4) were used to investigate if consistent alterations exist in multiple elements of the retinoic acid signaling pathway in these models. Many steps of the retinoic acid signaling pathway including binding proteins and metabolic enzymes decline, while the previously reported increase in RBP4 was only consistent at late (6 months) but not early (3 month) ages. The retinoic acid receptors were exceptional in their consistent decline in mRNA and protein with transcript decline of retinoic acid receptors β and γ by 3 months, before significant pathology, suggesting involvement in early stages of disease. Decline in RBP1 transcript may also be an early but not late marker of disease. The decline in the retinoic acid signaling system may therefore be a therapeutic target for AD and frontotemporal dementia. Thus, novel stable retinoic acid receptor modulators (RAR-Ms) activating multiple genomic and non-genomic pathways were probed for therapeutic control of gene expression in rat primary hippocampal and cortical cultures. RAR-Ms promoted the non-amyloidogenic pathway, repressed lipopolysaccharide induced inflammatory genes and induced genes with neurotrophic action. RAR-Ms had diverse effects on gene expression allowing particular RAR-Ms to be selected for maximal therapeutic effect. Overall the results demonstrated the early decline of retinoic acid signaling in AD and frontotemporal dementia models and the activity of stable and potent alternatives to retinoic acid as potential therapeutics.
Highlights
Alzheimer’s disease (AD) is a chronic multifactorial neurodegenerative disorder that is characterized by the accumulation of amyloid plaques and neurofib-rillary tangles, progressive memory impairment, and the deterioration of cognitive ability [1]
Gene expression of key retinoic acid signaling molecules in Alzheimer’s disease mouse models mouse models and analyzed by reverse transcription followed by quantitative polymerase chain reaction (qPCR)
ribonucleic acids (RNA) levels were standardized with respect to the appropriate reference RNA controls in each model and compared to levels in wild type mouse models (WT) which were set at 1
Summary
Alzheimer’s disease (AD) is a chronic multifactorial neurodegenerative disorder that is characterized by the accumulation of amyloid plaques and neurofib-. Rillary tangles, progressive memory impairment, and the deterioration of cognitive ability [1]. It is the most common cause of dementia and contributes to about 60% to 70% of all cases [2]. T. Khatib et al / Retinoic Acid Defect in Alzheimer’s Disease the central nervous system (CNS), but more recently evidence has accumulated on the importance of RA signaling in the adult CNS [4]. RA is known to be crucial for several aspects of neuroplasticity within the adult brain. Neuroplasticity is fundamental to the formation of new memories [6], and aspects of neuroplasticity promoted by RA are long-term potentiation/depression (LTP/LTD) [7], neurogenesis [8], homeostatic plasticity [9], and the capacity to form new neurites and neurite extensions [10]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
