Can we prevent AD by treating obesity?

In a recent study, it was determined that women who have been obese throughout their lives are more likely to lose brain tissue in the temporal lobe compared with women of normal weight (12).

In this paper, we highlight another aspect of neuroendocrine control of amyloidogenesis and risk for AD—a role for leptin as a modulator of Aβ homeostasis. It is well-established that brain lipids may be intricately involved in the amyloid cascade implicated in Alzheimer disease (2,3). This could be the basis for the action of leptin, a 16kDa peptide derived from a gene originally identified as a recessive mutant that causes obesity in the ob/ob mouse (1).

To investigate the potential link between leptin and AD, we treated human (SY5Y) or mouse neuroblastoma cell lines (Neuro2a, stably transfected to express the C-terminal fragment of APP) for 2-5 hours with 100-400 ng/ml leptin and determined its effect on amyloid precursor protein (APP) proteolytic processing. We found that this treatment caused a decrease in Aβ production. Further, these...  Read more

Can we prevent AD by treating obesity?

In a recent study, it was determined that women who have been obese throughout their lives are more likely to lose brain tissue in the temporal lobe compared with women of normal weight (12).

In this paper, we highlight another aspect of neuroendocrine control of amyloidogenesis and risk for AD—a role for leptin as a modulator of Aβ homeostasis. It is well-established that brain lipids may be intricately involved in the amyloid cascade implicated in Alzheimer disease (2,3). This could be the basis for the action of leptin, a 16kDa peptide derived from a gene originally identified as a recessive mutant that causes obesity in the ob/ob mouse (1).

To investigate the potential link between leptin and AD, we treated human (SY5Y) or mouse neuroblastoma cell lines (Neuro2a, stably transfected to express the C-terminal fragment of APP) for 2-5 hours with 100-400 ng/ml leptin and determined its effect on amyloid precursor protein (APP) proteolytic processing. We found that this treatment caused a decrease in Aβ production. Further, these treatments also increased the rate of ApoE-dependent uptake of Aβ, a process mediated through lipoprotein receptor-related protein (LRP) (4) contributing further to lowering extracellular Aβ. In contrast, treatment of SY5Y cells with cholesterol increased the secretion of Aβ, in agreement with previously published reports (2,3) and this was partially blocked by leptin. Leptin's action was mimicked by an inhibitor of acetyl CoA carboxylase (5) and fatty acid synthase (6). In contrast, a carnitine-palmitoyltransferase (7) inhibitor, increased Aβ production. Thus, amyloidogenic pathways are favored by anti-lipolytic/pro-lipogenic cascades and antagonized by pro-lipolytic/anti-lipogenic ones. In other words, a fat buildup/storage within neuronal cells could be harmful for the brain and its capacity to keep Aβ below toxicity levels. Our results suggest alternatives to statins as AD therapeutics.

We also determined plasma leptin levels in transgenic mice expressing both mutated amyloid precursor protein (APPSwe) and presenilin 1 (PS1) (8), and determined that in both males and females at 12 months of age, circulating plasma leptin levels were approximately half of those in wild-type littermates. Following chronic administration of leptin to the transgenic mice between 18 and 42 weeks of age, there was a noticeable decrease in the amyloid load (reduced Aβ in the hippocampus measured by ELISA and reduced amyloid plaque density, as evaluated by neuropathological examination of thioflavin S-stained brain sections). The highest difference in the amyloid load (observed even after 12 weeks of treatment) was between placebo-treated mice receiving a high-fat diet (highest load) and leptin-treated mice receiving a low-fat diet (lowest load).

The apparent leptin deficiency in these transgenic mice (also found in the Tg2576 mouse which is hemizygous for APPSwe (9)) may or may not be directly linked to the overproduction of Aβ in the CNS. However, chronic administration of leptin peripherally resulted in a significant reduction of the CNS amyloid load in these transgenic mice. Our results strongly support a role for leptin in the pathobiology of Alzheimer disease, perhaps in parallel or complementary to one proposed for insulin (10). Leptin receptors are present in both the hippocampus and olfactory bulb (11), brain areas affected early during the course of the disease, and a dysregulation of pathways associated with leptin may contribute to the neurodegeneration.

References:
1. Zhang, Y., Proenca, R., Maffei, M., Barone, M., Leopold, L., and Friedman, J. M. (1994) Positional cloning of the mouse obese gene and its human homologue. Nature 372, 425-432. Abstract

2. Simons, M., Keller, P., De Strooper, B., Beyreuther, K., Dotti, C. G., and Simons, K. (1998) Cholesterol depletion inhibits the generation of β-amyloid in hippocampal neurons. Proc Natl Acad Sci U S A 95, 6460-6464. Abstract

3. Refolo, L. M., Malester, B., LaFrancois, J., Bryant-Thomas, T., Wang, R., Tint, G. S., Sambamurti, K., Duff, K., and Pappolla, M. A. (2000) Hypercholesterolemia accelerates the Alzheimer's amyloid pathology in a transgenic mouse model. Neurobiol Dis 7, 321-331. Abstract

4. Tezapsidis, N., Merz, P., Merz, G., and Hong, H. (2003) Microtubular interactions of presenilin direct kinesis of Aβ peptide and its precursors. FASEB J. 17, 1322-1324. Abstract

5. Minokoshi, Y., Kim, Y. B., Peroni, O. D., Fryer, L. G., Muller, C., Carling, D., and Kahn, B. B. (2002) Leptin stimulates fatty-acid oxidation by activating AMP-activated protein kinase. Nature 415, 339-343. Abstract

6. Mobbs, C. V. M., H. Block the FAS, lose the fat. Nat Med. 2002 Apr;8(4):335-6. No abstract available. Abstract

7. Arduini, A., Denisova, N., Virmani, A., Avrova, N., Federici, G., and Arrigoni-Martelli, E. (1994) Evidence for the involvement of carnitine-dependent long-chain acyltransferases in neuronal triglyceride and phospholipid fatty acid turnover. J Neurochem 62, 1530-1538. Abstract

8. Holcomb, L., Gordon, M. N., McGowan, E., Yu, X., Benkovic, S., Jantzen, P., Wright, K., Saad, I., Mueller, R., Morgan, D., Sanders, S., Zehr, C., O'Campo, K., Hardy, J., Prada, C. M., Eckman, C., Younkin, S., Hsiao, K., and Duff, K. (1998) Accelerated Alzheimer-type phenotype in transgenic mice carrying both mutant amyloid precursor protein and presenilin 1 transgenes. Nat Med 4, 97-100. Abstract

9. Hsiao, K., Chapman, P., Nilsen, S., Eckman, C., Harigaya, Y., Younkin, S., Yang, F., and Cole, G. (1996) Correlative memory deficits, Aβ elevation, and amyloid plaques in transgenic mice. Science 274, 99-102. Abstract

10. Taubes, G. Neuroscience. Insulin insults may spur Alzheimer's disease. Science. 2003 Jul 4;301(5629):40-1. Abstract

11. Harvey, J. A., M.L. Leptin in the CNS: much more than a satiety signal. Neuropharmacology. 2003 Jun;44(7):845-54. Review. Abstract

12. Gustafson D, Lissner L, Bengtsson C, Bjorkelund C, Skoog I. (2004) A 24-year follow-up of body mass index and cerebral atrophy. Neurology. 63:1876-81. Abstract

View all comments by Nikolaos Tezapsidis

This manuscript demonstrates a fascinating link between lipid homeostasis and APP processing. Previous work shows that BACE activity is modulated by cholesterol, and loss of presenilins change the metabolism of long chain fatty acids. This manuscript adds to the link by showing that leptin and other modulators of lipid production also regulate Aβ production, and appear to do so by affecting BACE activity. Perhaps BACE plays a role in lipid homeostasis....

View all comments by Benjamin Wolozin

This is a thorough and fascinating report by Nikolas Tezapsidis that shows a clear association between leptin and Aβ levels, at least when leptin is introduced into a variety of experimental systems, including the Tg2576 mouse model. It will be important to determine whether these leptin-induced changes in Aβ levels result in improvements in learning and memory or in plaque deposition in this model. This study also sets the framework for a careful analysis between leptin levels and Aβ levels in humans.

View all comments by Christopher Eckman

Leaping on Leptin: What’s the Skinny?
The work by Fewlass and colleagues [1] provides an impressive array of data suggesting that leptin hormone homeostasis and/or dysregulation bears upon the metabolism of amyloid-β (Aβ). Although not confirmed by neuropathological examination, Tg2675 AD-transgenics appeared to show decreased levels of amyloid-β in brain homogenate following an eight-week subcutaneous administration of leptin. Leptin also appears to act as a stimulus for neuronal cells to uptake Aβ—more so with supplementation of exogenous apolipoprotein E. Thus, according to this data, leptin is able to modulate Aβ kinesis and extracellular concentrations.

As this work points out, the normal physiologic and pathologic roles of leptin in the brain deserve careful attention. As suggested by the authors, it may be that leptin serves a neuroprotective role and, as such, is worthy of therapeutic investigation. On the other hand, it has also been demonstrated that hyperleptinemia is a causative factor in obesity-related hypertension and vascular inflammation, and is...  Read more

Leaping on Leptin: What’s the Skinny?
The work by Fewlass and colleagues [1] provides an impressive array of data suggesting that leptin hormone homeostasis and/or dysregulation bears upon the metabolism of amyloid-β (Aβ). Although not confirmed by neuropathological examination, Tg2675 AD-transgenics appeared to show decreased levels of amyloid-β in brain homogenate following an eight-week subcutaneous administration of leptin. Leptin also appears to act as a stimulus for neuronal cells to uptake Aβ—more so with supplementation of exogenous apolipoprotein E. Thus, according to this data, leptin is able to modulate Aβ kinesis and extracellular concentrations.

As this work points out, the normal physiologic and pathologic roles of leptin in the brain deserve careful attention. As suggested by the authors, it may be that leptin serves a neuroprotective role and, as such, is worthy of therapeutic investigation. On the other hand, it has also been demonstrated that hyperleptinemia is a causative factor in obesity-related hypertension and vascular inflammation, and is able to induce systemic oxidative stress [2,3]—all potential risk factors for AD. Additionally, leptin also potentiates gonadotropin release in the hypothalamic-pituitary-gonadal axis [4,5,6] and we have previously hypothesized that elevated levels of gonadotropins are a risk factor in the development of AD [6,7]. Therefore, while the mechanism of leptin action in AD pathogenesis awaits further elucidation, the implications of this exciting paper may lead to the elevation of leptin as an important player in the growing tide of research dedicated to hormonal mechanisms in disease progression.

References:
1. Fewlass DC, Noboa K, Pi-Sunyer FX, Johnston JM, Yan SD, Tezapsidis N. Obesity-related leptin regulates Alzheimer's Abeta. FASEB J. 2004 Dec ; 18(15):1870-8. Abstract

2. Correia ML, Haynes WG. Leptin, obesity and cardiovascular disease. Curr Opin Nephrol Hypertens. 2004 Mar;13(2):215-23. Abstract

3. Beltowski J, Wojcicka G, Marciniak A, Jamroz A. Oxidative stress, nitric oxide production, and renal sodium handling in leptin-induced hypertension. Life Sci. 2004 Apr 30;74(24):2987-3000. Abstract

4. Cunningham M.J., Clifton D.K., Steiner R.A., Leptin´s actions on the reproductive axis: perspectives and mechanisms", Biol. Reprod., Volume: 60, (1999), pp. 216-222. Abstract

5. Islami D, Bischof P, Chardonnens D. Possible interactions between leptin, gonadotrophin-releasing hormone (GnRH-I and II) and human chorionic gonadotrophin (hCG). Eur J Obstet Gynecol Reprod Biol. 2003 Oct 10;110(2):169-75. Abstract

6. Amstalden M, Harms PG, Welsh TH Jr, Randel RD, Williams GL. Effects of leptin on gonadotropin-releasing hormone release from hypothalamic-infundibular explants and gonadotropin release from adenohypophyseal primary cell cultures: further evidence that fully nourished cattle are resistant to leptin. Anim Reprod Sci. 2005 Jan;85(1-2):41-52. Abstract

7. Smith MA, Perry G, Atwood CS, Bowen RL. Estrogen replacement and risk of Alzheimer disease. JAMA. 2003 Mar 5;289(9):1100. Abstract

8. Webber KM, Bowen R, Casadesus G, Perry G, Atwood CS, Smith MA. Gonadotropins and Alzheimer's disease: the link between estrogen replacement therapy and neuroprotection. Acta Neurobiol Exp (Wars). 2004;64(1):113-8. Abstract

View all comments by Matthew Garrett
View all comments by George Perry
View all comments by Mark A. Smith

Skinny Is Not as Weak as You Thought
Reply by Nikolaos Tezapsidis

I would like to thank all of you for your comments on our paper which describes a possible link between leptin and AD-related pathways. I would also like to take the opportunity to add further perspective.

It is true that exacerbation of inflammatory cascades attributable to hyperleptinemic conditions may appear to be cautionary of possible adverse effects of leptin (see comment by M. Garret, G. Perry, M. Smith above). This peptide, after all, has an Interleukin-6-like (proinflammatory cytokine) structure and function. Further, it has been suggested that similarly to the link between type II diabetes and insulin resistance, there is a link between obesity and leptin resistance (leptin is secreted by adipocytes in quantities directly proportional to adipose mass).

In other words, don’t just start injecting yourself with leptin; neither will you become thinner nor is it certain that it will prevent you from getting Alzheimer’s. However, treating an underlying obesity state and diabetes may...  Read more

Skinny Is Not as Weak as You Thought
Reply by Nikolaos Tezapsidis

I would like to thank all of you for your comments on our paper which describes a possible link between leptin and AD-related pathways. I would also like to take the opportunity to add further perspective.

It is true that exacerbation of inflammatory cascades attributable to hyperleptinemic conditions may appear to be cautionary of possible adverse effects of leptin (see comment by M. Garret, G. Perry, M. Smith above). This peptide, after all, has an Interleukin-6-like (proinflammatory cytokine) structure and function. Further, it has been suggested that similarly to the link between type II diabetes and insulin resistance, there is a link between obesity and leptin resistance (leptin is secreted by adipocytes in quantities directly proportional to adipose mass).

In other words, don’t just start injecting yourself with leptin; neither will you become thinner nor is it certain that it will prevent you from getting Alzheimer’s. However, treating an underlying obesity state and diabetes may help you maintain a healthier mind.

In moderation, leptin can sensitize insulin’s action, which can be beneficial for overall energy homeostasis and specifically for the CNS. For example, less insulin in the brain should result in more availability of Insulin Degrading Enzyme, an enzyme which also degrades Aβ. In addition, leptin can modulate hippocampal neuronal activity directly and Aβ homeostasis (our study). Leptin, like estrogen, drops dramatically in women postmenopausally, and this may contribute to the increased risk for Alzheimer’s among elderly women compared to men. Thus, women may be better candidates to benefit from a leptin therapy. An interesting interplay between leptin and the reproductive organs and sex hormones and the HPA may also exist that amplifies this deficiency and is worth investigating with regards to AD-linked pathological pathways.

We are very excited with the different avenues that have opened up with this seminal study and look forward to more interesting observations from our and other research laboratories.

View all comments by Nikolaos Tezapsidis

In a paper in the Journal of Alzheimer's Disease, we demonstrate that the oxysterol 27-hydroxycholesterol reduces leptin levels and increases levels of both Aβ and phosphorylated tau in organotypic slices from adult rabbit hippocampus. Interestingly, we show that treatment with leptin reversed the 27-OHC-induced increase in Aβ and phosphorylated tau by decreasing the levels of BACE-1 and GSK-3β, respectively. Our results suggest that cholesterol metabolites induce AD-like pathology by altering leptin signaling.

References:
Marwarha G, Dasari B, Prasanthi JR, Schommer J, Ghribi O. Leptin is Involved in Accumulation of Amyloid-beta and Tau Phosphorylation Induced by 27-Hydroxycholesterol in Organotypic Slices from Adult Rabbit Hippocampus. J Alzheimers Dis. 2009 Dec 7. Abstract

View all comments by Othman Ghribi