Obesity, leptin, and Alzheimer's disease

Abstract

Obesity has various deleterious effects on health largely associated with metabolic abnormalities including abnormal glucose and lipid homeostasis that are associated with vascular injury and known cardiac, renal, and cerebrovascular complications. Advanced age is also associated with increased adiposity, decreased lean mass, and increased risk for obesity-related diseases. Although many of these obesity- and age-related disease processes have long been subsumed to be secondary to metabolic or vascular dysfunction, increasing evidence indicates that obesity also modulates nonvascular diseases such as Alzheimer's disease (AD) dementia. The link between peripheral obesity and neurodegeneration will be explored, using adipokines and AD as a template. After an introduction to the neuropathology of AD, the relationship between body weight, obesity, and dementia will be reviewed. Then, population-based and experimental studies that address whether leptin modulates brain health and mitigates AD pathways will be explored. These studies will serve as a framework for understanding the role of adipokines in brain health.

Figure 1

Neuropathology of AD. Images from hematoxylin- and eosin-stained histologic sections (400× magnification) from affected human AD brain show: (A) granulovacuolar degeneration (arrowheads), (B) intracellular neurofibrillary tangles, and (C) waxy extracellular amyloid plaques. As neurofibrillary tangles and amyloid plaques are relatively subtle using routine stains, histologic diagnosis of AD is aided by using dyes that bind to amyloid structures or with antibodies specific for tau or Aβ(D) Thioflavin S staining (fluorescent green color, 100× magnification) of human AD necortex shows abundant extracellular amyloid plaques (arrows) and intraneuronal neurofibrillary tangles (arrowheads). Higher-power images (400× magnification) show (E) a neurofibrillary tangle and (F) an amyloid plaque. (G) Neurofibrillary tangles (arrows, 100×) are stained with antibodies that recognize phosphorylated tau protein epitopes. Note also the presence of clusters of phospho-tau immunoreactivity (circles) that label dystrophic neurites in association with amyloid plaques. (H) Amyloid plaques form in transgenic mouse overexpressing mutant APP that can be labeled with antibodies against Aβ (400× magnification).

Figure 2

Model of the clinical and biomarker progression of AD. Current efforts are underway to define the relationship between progression of AD (x-axis), various AD biomarkers (left y-axis), and clinical parameters associated with AD (right y-axis). Abnormal biomarker values related to the Aβ peptide (CSF Aβ measurements and/or amyloid dye imaging techniques, black line) indicate that abnormalities related to Aβ can be detected in presymptomatic individuals. Consequently, tau abnormalities and pathology may then develop (blue dotted line), followed by changes in brain structure and function (MRI and PET scans, purple dashed line). The onset of memory decline (empty green dotted line) heralds the clinical designation of “mild cognitive impairment” (MCI), which is typically followed by an overt decline in clinical function (empty red dashed line) and dementia, most commonly diagnosed as AD. Also reflected in this model is the association between obesity and dementia that is thought to occur in the presymptomatic phase of the disease as well as the association between weight loss (empty light blue line) and dementia that typically occurs close to and during the later stages of AD. Adapted and modified from work by Jack et al.

Figure 3

Leptin receptor signaling. LRb is constitutively associated with Janus family of tyrosine kinase 2 (JAK2). Leptin binding to LRb triggers autophosporylation of JAK2^– and subsequent phosphorylation of cytoplasmic LRb tyrosine residues, including Y1138 and Y985. Phosphorylation of Y1138 recruits STAT3, which is then phosphorylated and translocated into the nucleus to alter gene expression, including upregulation of suppressor of cytokine signaling 3 (SOCS3) expression.^, SOCS3 binds to Y985 as a negative feedback regulator of LRb signaling. Y985 serves dual roles in that its phosphorylation promotes binding of the tyrosine phosphatase SHP-2, leading to downstream Erk1/2 phosphorylation/activation.^, In cultured cells, LR activation also triggers phosphoinositide 3-kinase (PI3K)-Akt signaling,^,,, although it is unclear whether Akt phosphorylation occurs in vivo.^,– Both Erk1/2 (via p90RSK) and Akt phosphorylation can lead to downstream GSK3 phsophorylation/inhibition. Signaling molecules that are known to affect APP processing are highlighted in blue italics.