Alzheimers disease risk, obesity and tau: is insulin

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Le Freche H, Brouillette J,. Fernandez-Gomez FJ et al. Tau phosphorylation and sevoflurane anesthesia: an association to postoperative cognitive impairment.

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Alzheimer’s disease risk, obesity and tau: is insulin resistance guilty? Expert Rev. Neurother. 13(5), 461–463 (2013)

“…midlife development of obesity, a risk factor for insulin

David Blum Author for correspondence: Université Lille-Nord de France, UDSL, F-59000, Lille, France Inserm U837, Jean-Pierre Aubert Research Centre, IMPRT, F-59000, Lille, France CHRU-Lille, F-59000, Lille, France Tel.: +33 320 298 858 Fax: +33 320 538 562 [email protected]

Luc Buée Université Lille-Nord de France, UDSL, F-59000, Lille, France Inserm U837, Jean-Pierre Aubert Research Centre, IMPRT, F-59000, Lille, France CHRU-Lille, F-59000, Lille, France

resistance and diabetes, was described to increase the risk of dementia and Alzheimer’s disease later in life.” The definitive diagnosis of Alzheimer’s disease (AD) is essentially based on the observation of characteristic brain lesions following postmortem examination: β-amyloid deposits and neurofibrillary tangles. Neurofibrillary degeneration, found in more than 20 neurodegenerative disorders, referred to as tauopathies, consists in the intraneuronal accumulation, oligomerization and/or aggregation of hyper- and abnormally-phosphorylated tau proteins (‘tau pathology’) [1] . During aging, tau hyperphosphorylation is observed in the hippocampal formation. In AD, the propagation of the neurofibrillary lesions from the hippocampus to the temporal cortex, then other polymodal association areas and lastly the entire neocortex is correlated to the progression of the cognitive deterioration. These data suggest that pathological tau species are probably instrumental in several brain processes driving progressive memory loss in AD. This hypothesis is supported by compelling evidence that tau pathology is associated with several synaptic dysfunctions themselves important for memory formation. Such dysfunctions may arise from plasticity defects directly related to abnormal interaction of pathological tau species with synaptic proteins but also indirectly through tau-activated neuro-inflammatory processes [2,3] . Any modulation of tau pathology may thus affect cognitive abilities. Causes and factors impacting the risk of developing nonMendelian forms of AD are far from understood. From recent pan-genomic studies, we learn that several identified loci exhibit risk effects in large

populations of AD patients [101] . Different nongenetic risk factors have also been identified through cohort studies (caffeine consumption, exercise, stress etc.), some of them being shown to modulate tau [4,5] . Individual components of the metabolic syndrome have been linked to the risk of developing cognitive impairments and AD [6] . Furthermore, midlife development of obesity, a risk factor for insulin resistance and diabetes, was described to increase the risk of dementia and AD later in life. Accordingly, morbidly obese elderly individuals were found to exhibit AD-like neuropathological hallmarks [7] . While compelling evidence establishes a link between obesity and amyloidogenesis [8] , relationships to tau are pending. Diet-induced obesity in wild-type animals has been found to promote tau hyperphos­phorylation [9] but these observations remain inconsistent [10–12] . Reasons for such discrepancies remain obscure but they could eventually relate to the quality or duration of regimen, as previously suggested in the frame of hippocampal neuro-inflammation [13] . However, using a reliable tau transgenic mouse model (THY-tau22 strain), we recently demonstrated that progressive development of obesity worsens tau pathology and related cognitive disturbances [12] . These data experimentally support that while metabolic dysregulations associated to obesity may not be a triggering factor by themselves, they certainly favor the ­development of tau pathology over time. Insulin resistance is a metabolic compromise generally associated with obesity

Keywords: Alzheimer’s disease • obesity • tau


© 2013 Expert Reviews Ltd

ISSN 1473-7175



Blum & Buée

and favoring diabetes occurrence. Insulin resistance observed in nonobese diabetic mice or following peripheral injection of streptozotocine (STZ), a chemical compound toxic to pancreatic β-cells, leads to tau hyperphosphorylation [14,15] . In accordance, STZ was also shown to worsen tau phosphorylation and aggregation in the pR5 transgenic tau mouse model [16] . These data thus establish a link between peripheral insulin resistance and tau pathology. Underlying mechanisms relate mostly to phosphatase impairment but may also involve GSK3β activation [14,15] . Surprisingly, central insulin resistance has also been associated to tau dysfunctions. Intra-cerebral STZ injections in rats lead to impaired insulin signaling together with reduced tau binding to microtubules and tau hyperphosphorylation [17] . In accordance, the latter is also observed following conditional deletion of neuro­ nal insulin receptors [18] . These experimental studies support that defective insulin signaling described in postmortem brains from AD patients [19,20] is probably involved in the mechanisms leading to tau hyperphosphorylation and dysfunction. Whether or not obesity and associated peripheral insulin resistance are responsible for central insulin resistance and subsequent tau defects remains unclear. Obesity has been associated with defective brain insulin signaling in experimental models [9,11] and postmortem brains [20] . This could relate, at least in part, to peripheral hyperinsulinemia that has been proposed to impair brain insulin uptake. From that point of view, tau hyperphosphorylation could arise from defective central insulin signaling secondary to obesity-related peripheral insulin resistance. However, brain insulin resistance has been described in nonobese AD References 1





Sergeant N, Bretteville A, Hamdane M et al. Biochemistry of tau in Alzheimer’s disease and related neurological disorders. Expert Rev. Proteomics 5(2), 207–224 (2008). Burnouf S, Martire A, Derisbourg M et al. NMDA receptor dysfunction contributes to impaired brain-derived neurotrophic factor-induced facilitation of hippocampal synaptic transmission in a tau transgenic model. Aging Cell 12(1), 11–23 (2013). Blum D, Sandau U, Laurent C et al. Adenosine receptors in Alzheimer’s disease. In: Adenosine: a key link between metabolism and CNS activity. Masino S, Boison D (Eds) Springer, Berlin, Germany (2012). Belarbi K, Burnouf S, Fernandez-Gomez FJ et al. Beneficial effects of exercise in a transgenic mouse model of Alzheimer’s disease-like tau pathology. Neurobiol. Dis. 43(2), 486–494 (2011). Le Freche H, Brouillette J, Fernandez-Gomez FJ et al. Tau phosphorylation and sevoflurane anesthesia: an association to postoperative cognitive impairment. Anesthesiology 116(4), 779–787 (2012).


patients [19] . Furthermore, while some experimental data provide a link between central insulin resistance and tau hyperphosphorylation, the latter is not necessarily linked to peripheral insulin resistance and obesity. Indeed, recent postmortem observations demonstrate the absence of correlation between peripheral insulin resistance and neurofibrillary tangles [21] . Furthermore, our recent data demonstrate occurrence of tau pathology worsening in diet-induced obesity-treated tau mice in absence of both peripheral and central insulin resistance [12] . Obesity is thus undoubtedly a factor potentiating tau pathology but insulin resistance is probably not the missing link and factors involved remain to be identified. Recent pan-genomic [101] and experimental studies [4] highlight the importance of cholesterol metabolism regarding both AD risk and tau pathology. Contribution of dyslipidemia and cholesterol metabolism towards tau pathology during obesity is thus an interesting avenue to follow. Financial & competing interests disclosure

The authors were supported by the LabEx DISTALZ (Development of Innovative Strategies for a Transdisciplinary Approach to Alzheimer’s Disease), Fondation Coeur et Artères, Inserm, CNRS, DN2M, FEDER, France Alzheimer, Région Nord /Pas-de-Calais, LECMA, ANR (ADOR ATAU), ER A-Net NEURON, European Community (MEMOSAD; contract 200611) and FUI MEDIALZ. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.


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Alzheimer’s disease risk, obesity & tau: is insulin resistance guilty?



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Genes uncovered in Alzheimer’s disease genome-wide association studies.