Marginal vitamin A deficiency facilitates Alzheimer’s pathogenesis
- 2k Downloads
Deposition of amyloid β protein (Aβ) to form neuritic plaques in the brain is the unique pathological hallmark of Alzheimer’s disease (AD). Aβ is derived from amyloid β precursor protein (APP) by β- and γ-secretase cleavages and turned over by glia in the central nervous system (CNS). Vitamin A deficiency (VAD) has been shown to affect cognitive functions. Marginal vitamin A deficiency (MVAD) is a serious and widespread public health problem among pregnant women and children in developing countries. However, the role of MVAD in the pathogenesis of AD remains elusive. Our study showed that MVAD is approximately twofold more prevalent than VAD in the elderly, and increased cognitive decline is positively correlated with lower VA levels. We found that MVAD, mostly prenatal MVAD, promotes beta-site APP cleaving enzyme 1 (BACE1)-mediated Aβ production and neuritic plaque formation, and significantly exacerbates memory deficits in AD model mice. Supplementing a therapeutic dose of VA rescued the MVAD-induced memory deficits. Taken together, our study demonstrates that MVAD facilitates AD pathogenesis and VA supplementation improves cognitive deficits. These results suggest that VA supplementation might be a potential approach for AD prevention and treatment.
KeywordsMarginal vitamin A deficiency Alzheimer’s disease Amyloid β protein Memory deficits Vitamin A supplement
Amyloid β protein
Amyloid β precursor protein
Marginal vitamin A deficiency
This work was supported by grants from the National Natural Science Foundation of China (NSFC) Grant 30972461, 81161120498 (TL), and 81202291 (LC), and Canadian Institutes of Health Research (CIHR) Grant TAD-117948 (WS). WS is the holder of the Tier 1 Canada Research Chair in Alzheimer’s Disease. ZW is supported by the Alzheimer Society of Canada Postdoctoral Fellowship.
Compliance with ethical standards
Conflict of interest
The authors declare no conflict of interest.
- 2.Adlerz L, Beckman M, Holback S, Tehranian R, Cortés Toro V, Iverfeldt K (2003) Accumulation of the amyloid precursor-like protein APLP2 and reduction of APLP1 in retinoic acid-differentiated human neuroblastoma cells upon curcumin-induced neurite retraction. Mol Brain Res 119:62–72CrossRefPubMedGoogle Scholar
- 3.Bard F, Cannon C, Barbour R, Burke RL, Games D, Grajeda H, Guido T, Hu K, Huang J, Johnson-Wood K et al (2000) Peripherally administered antibodies against amyloid beta-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease. Nat Med 6:916–919CrossRefPubMedGoogle Scholar
- 14.Deng Y, Wang Z, Wang R, Zhang X, Zhang S, Wu Y, Staufenbiel M, Cai F, Song W (2013) Amyloid-beta protein (Abeta) Glu11 is the major beta-secretase site of beta-site amyloid-beta precursor protein-cleaving enzyme 1(BACE1), and shifting the cleavage site to Abeta Asp1 contributes to Alzheimer pathogenesis. Eur J Neurosci 37:1962–1969CrossRefPubMedGoogle Scholar
- 16.Donnen P, Dramaix M, Brasseur D, Bitwe R, Vertongen F, Hennart P (1998) Randomized placebo-controlled clinical trial of the effect of a single high dose or daily low doses of vitamin A on the morbidity of hospitalized, malnourished children. Am J Clin Nutri 68:1254–1260Google Scholar
- 19.Goncalves MB, Clarke E, Hobbs C, Malmqvist T, Deacon R, Jack J, Corcoran JP (2013) Amyloid beta inhibits retinoic acid synthesis exacerbating Alzheimer disease pathology which can be attenuated by an retinoic acid receptor alpha agonist. Eur J Neurosci 37:1182–1192CrossRefPubMedPubMedCentralGoogle Scholar
- 35.Liu X, Cui T, Li Y, Wang Y, Wang Q, Li X, Bi Y, Wei X, Liu L, Li T et al (2014) Vitamin A supplementation in early life enhances the intestinal immune response of rats with gestational vitamin A deficiency by increasing the number of immune cells. PLoS One 9:e114934CrossRefPubMedPubMedCentralGoogle Scholar
- 48.Ross AC, Harrison EH (2013) Vitamin A: nutritional aspects of retinoids and carotenoids. In: Zempleni J, Suttie JW, Gregory JF III, Stover PJ (eds) Handbook of vitamins, 5th edn. CRC Press, Boca Raton, pp 1–50Google Scholar
- 51.Sommer A, West KP (1996) Vitamin A deficiency: health, survival and vision. Oxford University Press, OxfordGoogle Scholar
- 64.WHO (2009) Global prevalence of vitamin A deficiency in populations at risk 1995–2005: WHO Global Database on Vitamin A Deficiency. WHOGoogle Scholar
- 65.WHO (2011) Guideline: Vitamin A supplementation for infants and children 6-59 months of age. WHOGoogle Scholar
- 66.WHO, UNICEF, IVACG Task Force (1997) Vitamin A supplements: a guide to their use in the treatment and prevention of vitamin A deficiency and xerophthalmia, 2nd edn. WHOGoogle Scholar
- 68.Wu Y, Deng Y, Zhang S, Luo Y, Cai F, Zhang Z, Zhou W, Li T, Song W (2015) Amyloid-beta precursor protein facilitates the regulator of calcineurin 1-mediated apoptosis by downregulating proteasome subunit alpha type-5 and proteasome subunit beta type-7. Neurobiol Aging 36:169–177CrossRefPubMedGoogle Scholar
- 73.Zhu Z (2011) The first 1000 days in life: changing life, changing future. Chin J Child Health Care 19:681–682Google Scholar