Marginal vitamin A deficiency facilitates Alzheimer’s pathogenesis

Abstract

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.

BACE2, a conditional β-secretase, contributes to Alzheimer’s disease pathogenesis

“…C99 is then cleaved by γ-secretase at the transmembrane domain to shed the N-terminal fragment Aβ. Mutations enhancing β-cleavage of APP or altering γ-cleavage of C99 result in early-onset AD (3)(4)(5). Recently, a missense mutation in the APP gene was shown to suppress Aβ production and reduce the risk of AD (3,6,7).…”

Vitamin A Deficiency Induces Autistic‐Like Behaviors in Rats by Regulating the RARβ‐CD38‐Oxytocin Axis in the Hypothalamus

“…All trans retinoic acid (atRA) is the functional form of VA in the body, and atRA plays an important role in the maturation of the central nervous system (CNS) during embryonic development by activating transcriptional factors, including retinoic acid (RA) nuclear receptors (RARs/RXRs) . Our previous studies have shown that gestational VAD impaired learning and memory skills in gestational VAD pups and that marginal VAD in early life could facilitate the pathogenesis of Alzheimer's disease . Our studies indicate that VA is involved in the pathogenesis of neurological diseases.…”

Formaldehyde induces diabetes‐associated cognitive impairments

“…AD is the most common neurodegenerative disorder leading to dementia, and its pathologic features include amyloid plaques and neurofibrillary tangles (31)(32)(33). Cognitive decline is one of the major consequences of diabetes, and growing evidence supports a strong link between AD-related dementia and diabetes (24,(34)(35)(36)(37). The prevalence of mild cognitive impairments is dramatically increased in individuals with diabetes (38,39), and diabetes also significantly accelerates the progression from mild cognitive impairments to dementia (40).…”

“…Mice with blood glucose levels .13 mM were considered diabetic. After 6 wk of treatment, the Morris water maze test was performed as previously described (24).…”