Having either an ApoE4 allele or Type 2 diabetes raises the risk of Alzheimer’s disease. A new paper in the March 8 Scientific Reports now suggests these factors can work together to bring on cognitive decline. Researchers led by Jacob Raber at Oregon Health and Science University, Portland, fed transgenic mice carrying human ApoE alleles a high-fat diet that caused them to gain weight and develop insulin resistance, a sign of diabetes. While all the tubby mice had problems with learning and memory, animals that carried an ApoE4 allele fared worse. Moreover, using a combination of unbiased metabolomics and epigenetics, the authors identified three key pathways related to glucose metabolism that were perturbed only in the insulin-resistant E4s. Intriguingly, one month of a low-fat diet was enough to restore both metabolism and memory to normal in these mice.
The results suggest that people who carry an ApoE4 allele might want to be particularly diligent about eating a healthy diet, Raber noted. “We’re all different, so an environmental challenge like a high-fat diet doesn’t affect everybody the same way,” he told Alzforum.
Commenters said these data shed more light on how the ApoE4 allele contributes to AD. William Rebeck at Georgetown University in Washington, D.C., found it particularly interesting that ApoE4 produced these effects in the absence of any amyloid pathology. “This demonstrates that ApoE could increase your risk of AD by affecting how well your brain metabolizes glucose into important compounds,” Rebeck suggested.
Energy Problems? Three pathways most affected in diabetic ApoE4 mice relate to energy metabolism. [Courtesy of Johnson et al., Scientific Reports.]
Diabetes heightens the risk of AD, and various studies have linked insulin resistance to the pathogenesis of the disease (for review see de la Monte, 2012; AlzRisk). Some previous studies suggested that ApoE4 carriers with diabetes run a higher risk of cognitive impairment and dementia than noncarriers (see Research Timeline 2012; Dore et al., 2009). Imaging studies have found that by the time they are in their 20s, healthy ApoE4 carriers already show signs of brain hypometabolism in the same regions typically affected by AD (Reiman et al., 2004).
To explore the interaction of ApoE genotypes with diabetes, the authors used ApoE3 and ApoE4 targeted replacement mice, which have human isoforms in place of the mouse gene. First author Lance Johnson fed nine-month-old animals chow that was 60 percent fat based on calories. This diet has been shown to induce insulin resistance and obesity in these animals, mimicking Type 2 diabetes. Control mice obtained only 10 percent of calories from fat. Both diets contained the same number of calories. People eating a typical Western diet get 35 to 45 percent of their calories from fat.
After six months on the high-fat regimen, the E3s and E4s both gained weight, but curiously, the E4s ended up less plump than the E3s. Both mouse models had similarly poor memory compared to controls in tests of novel object recognition and cued fear learning. However, E4s had more trouble learning the location of a hidden platform in the Morris water maze than did E3s, indicating their spatial memory was worse.
The authors analyzed hippocampal epigenetic and metabolomic changes in the mice, looking for pathways most altered in E4s eating the high-fat diet. They found thousands of methylated DNA regions that were unique to the overfed E4s, and were predicted to affect genes involved in numerous cellular processes. Among metabolites, 58 were altered by ApoE genotype and diet, falling into several pathways. In the combined epigenetic/metabolomic dataset, three pathways stood out: purine metabolism, glutamate metabolism, and the pentose phosphate pathway (see image above). All of these processes relate to energy metabolism.
The purine adenosine forms the basis of the energy source ATP. Purine metabolism has previously been reported to go awry in AD (see Sims et al., 1998; Ansoleaga et al., 2015). Purine biosynthesis also produces glutamate as a byproduct. This neurotransmitter links neuronal activity to glucose use, and is found in short supply in ApoE4 mice (see Dumanis et al., 2013). The pentose phosphate pathway (PPP), an alternative to glycolysis, metabolizes sugars to generate five-carbon precursors for various synthesis reactions, including purines. The PPP also helps lower oxidative stress, and is impaired in AD brains (see Palmer et al., 1999; Orešič et al., 2011). However, the mechanisms that connect ApoE4 to any of these processes remain unclear.
The authors wondered whether the harmful changes in memory and metabolism were reversible. They fed a separate group of nine-month-old ApoE4 mice a high-fat diet for five months, followed by a low-fat diet for one. Upon changing diets, the portly mice lost weight and could better metabolize sugar. In cognitive tests, the slimmed-down mice performed like normal controls. Epigenetic markers and metabolites also returned to normal.
Commenters found this improvement encouraging. “The data suggest that mindful lifestyle measures may protect ApoE4 carriers from late-onset mild cognitive impairment and AD,” Suzanne de la Monte wrote to Alzforum (see full comment below).
In ongoing work, Raber is testing other ways to rescue performance, such as injecting glucose into overfed ApoE4 mice to specifically boost brain levels of the sugar. “We see some protective effects,” he told Alzforum. While giving sugar to diabetic mice might seem counterintuitive, Raber noted that the brains of these animals appear to have trouble taking up glucose, perhaps causing the observed hypometabolism. He will also investigate whether injecting glucose right before a memory trial has benefits. “The question is, how fast do changes in metabolism occur?” he asked.
Other researchers noted the need for more mechanistic work to determine how ApoE influences metabolism. They also suggested the results should be repeated in a different strain of ApoE knock-ins to make sure these findings are broadly applicable. The knock-ins used in this study are in a C57BL/6 mouse background, and this strain is known to be highly susceptible to diet-induced obesity, de la Monte noted.—Madolyn Bowman Rogers
Research Models Citations
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- Dumanis SB, Dibattista AM, Miessau M, Moussa CE, Rebeck GW. APOE genotype affects the pre-synaptic compartment of glutamatergic nerve terminals. J Neurochem. 2012 Aug 3; PubMed.
- Palmer AM. The activity of the pentose phosphate pathway is increased in response to oxidative stress in Alzheimer's disease. J Neural Transm (Vienna). 1999;106(3-4):317-28. PubMed.
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- Johnson LA, Torres ER, Impey S, Stevens JF, Raber J. Apolipoprotein E4 and Insulin Resistance Interact to Impair Cognition and Alter the Epigenome and Metabolome. Sci Rep. 2017 Mar 8;7:43701. PubMed.