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...  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...  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
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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

Having been a neurologist in a former life, I have always wondered about how much aging plays a role in the neurodegenerative disorders. For some time it seemed that the debate (for it was a debate with little real information) fell into two categories. One point of view was that neurodegeneration is a disease and not a part of the normal aging process. The other viewpoint held that while it is a disease, it is age-related, so that the process of aging will impinge upon the timing and severity of the disorder. Some would go further to say that if people lived long enough, they would develop the neurodegenerative disorder, too. I think that these distinctions are less clear now. There certainly are a number of genetic and environmental factors that impinge upon the functioning and maintenance of the nervous system.

With regards to the Blueher et al. article, I think it is reasonable to assume that the aging process does impact strongly on neurodegenerative diseases, and interventions that either delay or slow down the aging process, or lead to a more healthy state, will...  Read more

Having been a neurologist in a former life, I have always wondered about how much aging plays a role in the neurodegenerative disorders. For some time it seemed that the debate (for it was a debate with little real information) fell into two categories. One point of view was that neurodegeneration is a disease and not a part of the normal aging process. The other viewpoint held that while it is a disease, it is age-related, so that the process of aging will impinge upon the timing and severity of the disorder. Some would go further to say that if people lived long enough, they would develop the neurodegenerative disorder, too. I think that these distinctions are less clear now. There certainly are a number of genetic and environmental factors that impinge upon the functioning and maintenance of the nervous system.

With regards to the Blueher et al. article, I think it is reasonable to assume that the aging process does impact strongly on neurodegenerative diseases, and interventions that either delay or slow down the aging process, or lead to a more healthy state, will either reduce or ameliorate many of the neurodegenerative disorders.

With regard to our work, the statement Bluher et al. make [about mitochondrial rate reduction extending life] we now know to be somewhat incorrect. Indy (for I’m not dead yet) long-lived flies have normal metabolic rates. At the time we published the Indy paper (Rogina et al., 2000), we did not know how a reduction in INDY led to life span extension. It was reasonable for Bluher et al. to think that the INDY protein is related to the mitochondria and would lead to a reduction in metabolism. However, we now know this not to be the case. The life-extending INDY protein is found on the plasma membrane, not the mitochondria (published last October, see Knauf et al, 2002), and in a paper in PNAS (see Marden et al., 2003), we show that the metabolic rate and physical activity of Indy long-lived flies is normal.

Regarding the question of whether metabolism and ROS reduction mediate the beneficial effect of caloric restriction, for me the issue is how does caloric restriction really lead to life span extension? There are clearly many different effects seen in a calorically restricted animal. Which ones are relevant to life span extension and which are associated with the restricted calorie state, but do not contribute to the life span change? One way of looking at the Bluher et al. paper is that an effect on fat tissue may be a direct downstream part of the pathway from caloric restriction to life span extension. For me, since no one knows the pathway or mechanism by which caloric restriction causes life span extension, there is a lot of room for speculation.

View all comments by Stephen Helfand

The analyses of mice with adipose cell-specific knockout of the insulin receptor (FIRKO mice) by Bluher et al. provide at least three major advances in our understanding the mechanisms whereby insulin signaling and energy metabolism regulate life span. First, they show that the life span of mice with impaired adipose insulin signaling is increased without a decrease in calorie intake. This result seemingly shatters the hypothesis that caloric restriction extends life span simply by reducing mitochondrial metabolism and oxyradical production. Second, their findings suggest that insulin signaling in different cell types may have different effects on overall energy metabolism and life span. These findings are intriguing and support possibly related findings of Wolkow et al., 2000, who showed that insulin signaling in the nervous system regulates life span in C. elegans. It remains unclear how insulin signaling in adipose cells reduces life span, but this is certainly an important area for further...  Read more

The analyses of mice with adipose cell-specific knockout of the insulin receptor (FIRKO mice) by Bluher et al. provide at least three major advances in our understanding the mechanisms whereby insulin signaling and energy metabolism regulate life span. First, they show that the life span of mice with impaired adipose insulin signaling is increased without a decrease in calorie intake. This result seemingly shatters the hypothesis that caloric restriction extends life span simply by reducing mitochondrial metabolism and oxyradical production. Second, their findings suggest that insulin signaling in different cell types may have different effects on overall energy metabolism and life span. These findings are intriguing and support possibly related findings of Wolkow et al., 2000, who showed that insulin signaling in the nervous system regulates life span in C. elegans. It remains unclear how insulin signaling in adipose cells reduces life span, but this is certainly an important area for further investigation. One possibility is stimulation by insulin of the release of hormones, lipids or other molecules that have a pro-aging effect.

Third, their data help to clarify an apparent contradiction between previous studies of insulin signaling and life span regulation in nematodes and rodents. Studies of C. elegans had shown that insulin signaling reduces life span, whereas increased insulin sensitivity (on a body-wide basis) is associated with increased life span in mammals. Caloric restriction, which extends life span, enhances insulin sensitivity in skeletal muscle while reducing fat mass. A generally similar increase in insulin sensitivity of nonadipose cells appears to occur in the FIRKO mice, although this needs to be examined in considerable detail. The initial phenotypes of FIRKO mice described in the study of Bluher et al. are remarkable, and suggest that these mice will provide a much-needed novel animal model for studies of mechanisms of aging and age-related disease.

View all comments by Mark Mattson

Abandon your diets! Kahn and colleagues have examined the impact of selective loss of insulin receptors in adipose tissue on longevity in FIRKO (fat-specific insulin receptor knockout) mice. Disruption of insulin signaling appears not to be associated with diabetes or glucose intolerance. In addition, such mice have reduced fat mass, eat normally, and do not develop age-related obesity, which results in an overall extended mean life span.

In the nematode and the fruit fly, decreased insulin-like signaling also appears to extend life span. Conversely, in mammals and humans, severe disruption of the insulin receptor leads to insulin resistance associated with diabetes and obesity, which extrapolates to a shortened life span. The FIRKO mouse exhibits loss of insulin signaling in fat tissue only. Together with normal food intake and reduced overall adiposity, the authors propose the FIRKO mouse as an in vivo model for mimicking caloric restriction. Although not investigated, the reduction in fat mass is likely due to an increased metabolic rate. However in rodents, caloric...  Read more

Abandon your diets! Kahn and colleagues have examined the impact of selective loss of insulin receptors in adipose tissue on longevity in FIRKO (fat-specific insulin receptor knockout) mice. Disruption of insulin signaling appears not to be associated with diabetes or glucose intolerance. In addition, such mice have reduced fat mass, eat normally, and do not develop age-related obesity, which results in an overall extended mean life span.

In the nematode and the fruit fly, decreased insulin-like signaling also appears to extend life span. Conversely, in mammals and humans, severe disruption of the insulin receptor leads to insulin resistance associated with diabetes and obesity, which extrapolates to a shortened life span. The FIRKO mouse exhibits loss of insulin signaling in fat tissue only. Together with normal food intake and reduced overall adiposity, the authors propose the FIRKO mouse as an in vivo model for mimicking caloric restriction. Although not investigated, the reduction in fat mass is likely due to an increased metabolic rate. However in rodents, caloric restriction appears to extend life span without altering metabolic rate. Well-established evidence supports beneficial effects of caloric restriction on aging and age-related diseases in several animal models, but the precise mechanisms of how or why this occurs remain unclear. It seems likely that leanness, rather than food restriction per se, may be the key element in increasing lifespan in FIRKO mice.

Although preliminary, this study has broad implications. A 30 percent food-restricted diet is extremely unlikely to become a widespread practice among the general population without the aid of a caloric restriction mimetic agent. This study presents novel and exciting findings, which suggest that the anti-aging protective effects of caloric restriction might be achievable by indirect mechanisms, eliminating the need to diet.

View all comments by TracyAnn Perry

The paper from Kahn and coworkers is interesting and deserves greater attention. The expanded life expectancy due to leanness caused by a selective loss of insulin signalling in adipose tissue may point to an active metabolic role of that tissue. In this respect, work of other people suggests that leptin derived from adipose tissue may be involved in this process, see JF Caro et al., 1996; A Haman et al., 1996; B Ahren et al., 1997; J Auwerx, B Staels, 1998; G Chen et al., 1996; N Barzilai et al., 1997. However, one important question remains unanswered: Is extended longevity accompanied by a stable quality of life, particularly with regard to mental health? It is tempting to asssume some relationship between Kahn's data and sporadic AD. In...  Read more

The paper from Kahn and coworkers is interesting and deserves greater attention. The expanded life expectancy due to leanness caused by a selective loss of insulin signalling in adipose tissue may point to an active metabolic role of that tissue. In this respect, work of other people suggests that leptin derived from adipose tissue may be involved in this process, see JF Caro et al., 1996; A Haman et al., 1996; B Ahren et al., 1997; J Auwerx, B Staels, 1998; G Chen et al., 1996; N Barzilai et al., 1997. However, one important question remains unanswered: Is extended longevity accompanied by a stable quality of life, particularly with regard to mental health? It is tempting to asssume some relationship between Kahn's data and sporadic AD. In their textbooks published around 150 years and 100 years ago, Lorenz Geist, Emil Kraepelin, and Eugen Bleuler described the "classical" AD patient as being lean to gaunt in spite of normal to supernormal food intake. Provided that in sporadic AD, the observed disturbance in insulin signaling is not limited to neuronal tissue but also occurs in adipose tissue, a more general abnormality in insulin signaling in sporadic AD may be assumed. Studies on adipose tissue should clarify this issue.

Reference:
Bluher M, Kahn BB, Kahn CR. Extended longevity in mice lacking the insulin receptor in adipose tissue. Science. 2003 Jan 24;299(5606):572-4. Abstract

View all comments by Siegfried Hoyer

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