Vitamin D3 Promotes the Recovery of Abeta Phagocytosis in Defective AD Macrophages

A very recent paper1 reports that 1alpha,25(OH)2-vitamin D3 (1,25D3) activation of the Vitamin D receptor (VDR), via genomic (gene expression) and nongenomic signaling, promotes the recovery of amyloid-beta phagocytosis by faulty Alzheimer’s disease macrophages. The authors note that, “[i]n support of this hypothesis, nutritional supplementation with vitamin D3 has been shown to protect against cognitive decline in elderly subjects.”1b

Vitamin D3 has also been reported to have other neuro­protective effects. For example, one paper1c found that vitamin D3 attenuated damage induced by the powerful neurotoxin 6-hydroxydopamine in rats.

A Curcuminoid Found in Turmeric Increased Vitamin D3 Enhanced Amyloid Beta Clearance

Alzheimer’s disease (AD) patients have defective clearance of amyloid beta by phagocytosis normally performed by peripheral blood mononuclear cells (PBMCs), as well as defective clearance via the autophagic-lysosomal pathways in AD fibroblasts and neurons. The finding by the authors of paper #1 that vitamin D3 stimulates the recovery of phagocytosis by AD macrophages of amyloid beta-42 was reported by them in an earlier paper.2 In that earlier paper, the researchers also reported that bisdemethoxycurcumin, a form of curcumin found naturally in turmeric root, additively stimulated (with 1,25 D3) phagocytosis of amyloid beta-42 by type I AD macrophages. (AD macrophages have been reported by these authors to be subdivided into three types—type I, type II, and type 0—depending upon their expression of MGAT3, a gene which the authors say plays a “critical” role in phagocytosis.) They didn’t offer a hypothesis on why the curcuminoid was able to promote phagocytosis in only type I of the AD macrophages, while 1,25 D3 did so in both type I and type II AD macrophages. However, the type I macrophages are said to be the type found in the majority of AD patients.3 By using a specific inhibitor of the 1,25 D3-vitamin D receptor, the researchers2 were able to show that phagocytosis of amyloid beta in patients with type I and type II macrophages was dependent on 1,25 D3.

Curcuminoids Have Neuroprotective Effects

Curcuminoids have been reported to have neuroprotective effects in other papers. See, for example, paper #4 in the references below. In that recent paper, curcuminoids (curcumin, demethoxycurcumin, and bisdemethoxycurcumin) promoted neurite outgrowth from PC12 cells (a rat pheochromocytoma cell line) via complex signaling involving MAPK/ERKand PKC-dependent pathways. As noted in this paper, “neurotrophic factors are attractive candidates for therapeutic agents in chronic neurodegenerative diseases and acute injuries including trauma and stroke.”4

Curcumin was also reported to inhibit formation of amyloid beta fibrils4a and to reduce indices of oxidative stress and inflammation that are associated with AD in the brains of APPs mice (mice genetically engineered to produce high levels of soluble amyloid precursor protein).4b

… And Also Enhance Phagocytosis of Amyloid Beta by Macrophages from AD Patients

An earlier paper5 by the same group that published the work on vitamin D3 and curcuminoids described above reported on the treatment of peripheral blood monunuclear cells (PBMC) from six AD patients with curcuminoids (a proprietary curcumin complex) and compared the cells’ phagocytosis of amyloid beta with PBMCs from three normal controls. Phagocytosis was significantly increased in three of the six AD patients by curcuminoids, with the optimal concentration enhancing phagocytosis being 0.1 μM curcuminoids. The increase in amyloid beta uptake was through induction of intracellular phagocytosis by curcuminoids as revealed by confocal microscopy (as opposed to surface binding in untreated macrophages). The macrophages of control patients were also treated with curcuminoids but they already had a high amyloid beta uptake at baseline and their uptake was not further enhanced by curcuminoid treatment.

Critical Importance of Clearing Amyloid Beta From the Brain

“The most common form of Alzheimer’s disease [AD] occurs sporadically late in life and is typified by deposition of amyloid beta (Abeta) within the brain. Individuals with late-onset AD produce Abeta peptides at normal levels but have an impaired ability to clear them from the br ain.”a In fact, late-onset AD patients were observed in one studya2 to have a 30% decrease in amyloid beta clearance as compared to controls. The authorsa2calculated that this diminishment of amyloid beta metabolism is consistent with an ~10 year timeframe for the buildup of the amyloid beta in the disease. (The clearance rates were determined by collecting cerebral spinal fluid from individuals infused with 13C6-leucine to label newly synthesized proteins.)

One of the toxic effects that result from the accumulation of Abeta peptide oligomers, for example, is the reported inhibition by about 50% of choline acetyltransferase, the enzyme responsible for chemically converting choline to acetylcholine, in cultured cholinergic neurons exposed to low nanomolar concentrations of Abeta peptide oligomers.b Acetylcholine is a neurotransmitter critically important in learning and memory, muscular contraction, as a signaling molecule for release of nitric oxide in endothelial vasodilation, as well as in many other functions.

Recent studies have focused on the importance of clearing amyloid beta from the brain. For example, a recent papera reported on an FDA approved drug (Bexarotene) that was able to reduce Abeta plaque area in a mouse model of AD by more than 50% within just 72 hours. In fact, the drug was reported to cause a rapid reversal of cognitive, social, and olfactory deficits and improved neural circuit function in the AD mice. The drug is an agonist of (activates) the retinoid X receptor (RXR) that facilitated the clearance of Abeta by enhancing the activation of ApoE (important in the clearance of Abeta) and promoting microglial phagocytosis via the activation of a complex interaction between PPARgamma:RXR and LXR(liver X receptor):RXR. Two of the authors of the paper on Bexarotenea hold U.S. Provisional Patent Application No. 61/224,709 regarding use of the drug as a potential therapeutic for AD and are founding scientists of ReXceptor, Inc., which has licensing options from Case Western Reserve University on the use of Bexarotene in the treatment of AD. The drug as used for its current FDA approved indication is said to display a favorable side effect profile.

† Bexarotene is approved for the treatment of cutaneous manifestations of cutaneous T-cell lymphoma in patients who are refractory to at least one prior systemic therapy. (Physicians’ Desk Reference, --2011) 

‡ Mandrekar-Colucci & Landreth. Nuclear receptors as therapeutic targets for Alzheimer’s disease,” Expert Opin Ther. Targets15(9):1085-97 (2011).

If You’ve Read This Far, You’ve Passed the Test!

Well, OK, there really wasn’t any test, but we figure that if you have read to this point, your cognitive abilities are likely to be in good condition, but it is always prudent to take no chances on them staying that way. The two of us take daily supplements of vitamin D3 and turmeric root powder (which contains a variety of curcuminoids), among other supplements, as a sensible precaution6-10 against age-associated cognitive decline.


  1. Cramer et al, “ApoE-directed therapeutics rapidly clear beta amyloid and reverse deficits in AD mouse models,”Science335:1503-1506 (2012).
    a2. Mawuenyaga et al, Decreased clearance of CNS beta-amyloid in Alzheimer’s disease. Science 330:1774 (2010).
    b. Nunes-Tavares et al. Inhibition of choline acetyltransferase as a mechanism for cholinergic dysfunction induced by amyloidbeta peptide oligomers. J Biol Chem287(23):19377-85 (2012). 
    1. Mizwicki et al. Genomic and nongenomic signaling induced by 1alpha,25(OH)2-vitamin D3 promotes the recovery of amyloid-beta phagocytosis by Alzheimer’s disease macrophages. J Alzheimers Dis 29:51-62 (2012).
    1b. Llewellyn et al. Vitamin D and risk of cognitive decline in elderly persons,” Arch Intern Med 170:1135-41 (2010). 
    1c. Wang et al. Vitamin D3 attenuates 6-hydroxydopamine-induced neurotoxicity in rats,” Brain Res 904(1):67-75 (2001). 
    2. Fiala et al. MGAT3 mRNA: a biomarker for prognosis and therapy of Alzheimer’s disease by vitamin D and curcuminoids. J Alzheimers Dis 25:135-44 (2011) 
    3. Avagyan et al. Immune blood markers of Alzheimer disease patients. J Neuroimmunol 210:67-72 (2009). 
    4. Liao et al. Curcuminoids promote neurite outgrowth in PC12 cells through MAPK/ERKand PKC-dependent pathways. J Agric Food Chem 60:433-43 (2012).
    4a. Ono et al. Curcumin has potent anti-amyloidogenic effects for Alzheimer’s beta-amyloid fibrils in vitro. J Neurosci Res 75:742-50 (2004). 
    4b. Lim et al. The curry spice curcumin reduces oxidative damage and amyloid pathology in an Alzheimer transgenic mouse. J Neurosci 21:8370-7 (2001).
    5. Zhang et al. Curcuminoids enhance amyloid-beta uptake by macrophages of Alzheimer’s disease patients. J Alzheimers Dis 10:1-7 (2006).
    6. Hathcock et al. Risk assessment for vitamin D. Am J Clin Nutr 85:6-18 (2007). “Collectively, the absence of toxicity in trials conducted in healthy adults that used vitamin D dose ≥250 ug/d (10,000 iu vitamin D3) supports the confident selection of this value as the UL [upper limit].” 
    7. Murff. Review: Cholecalciferol (vitamin D3) reduces mortality in adults; other forms of vitamin D do not. Ann Intern Med 155(5):JC5-4 (15 Nov. 2011). 
    8. Lee et al. Vitamin D rejuvenates aging eyes by reducing inflammation, clearing amyloid beta and improving visual function. Neurobiol Aging doi:10.1016/j.neurobiolaging.2011.12.002. 
    9. Moore et al. Evidence that vitamin D3 reverses age-related inflammatory changes in the rat hippocampus,” Biochem Soc Transactions 33 part 4:573-7 (2005).
    10. Zhang et al. Curcumin decreases amyloid-beta peptide levels by attenuating the maturation of amyloid-beta precursor protein. J Biol Chem 285(37):28472-80 (2010).