Brain insulin and insulin receptors in aging and sporadic Alzheimer's disease

Abstract

The search for the causes of neurodegenerative disorders is a major theme in brain research. Acquired disturbances of several aspects of cellular metabolism appear pathologically important in sporadic Alzheimer's disease (SDAT). Among these brain glucose utilisation is reduced in the early stages of the disease and the regulatory enzymes important for glucose metabolism are reduced. In the brain, insulin, insulin-like growth factors and their receptors regulate glucose metabolism and promote neuronal growth. To detect changes in the functional activity of the brain insulin neuromodulatory system of SDAT patients, we determined the concentrations of insulin and c-peptide as well as insulin receptor binding and IGF-I receptor binding in several regions of postmortem brain cortex during aging and Alzheimer's disease. Additionally, we performed immunohistochemical staining with antibodies against insulin in neocortical brain areas in SDAT and controls. We show for the first time that insulin and c-peptide concentration in the brain are correlated and decrease with aging, as do brain insulin receptor densities. Weak insulin-immunoreactivity could be demonstrated histochemically in pyramidal neurons of controls, whereas in SDAT a stronger insulin-immunoreactivity was found. On a biochemical level, insulin and c-peptide levels were reduced compared to middle-aged controls, but were unchanged compared to age-matched controls. Brain insulin receptor densities in SDAT were decreased compared to middle-aged controls, but increased in comparison to age-matched controls. IGF-I receptor densities were unchanged in aging and in SDAT. Tyrosine kinase activity, a signal transduction mechanism common to both receptor systems, was reduced in SDAT in comparison to middle-aged and age-matched control groups. These data are consistent with a neurotrophic role of insulin in the human brain and a disturbance of insulin signal transduction in SDAT brain and favor the hypothesis that insulin dependent functions may be of pathogenetic relevance in sporadic SDAT.

Insulin Receptor Dysfunction Impairs Cellular Clearance of Neurotoxic Oligomeric Aβ

“…Conversely, dysfunctional IR mutants that manifest insulin resistance syndrome in clinic, or pharmacological inhibition of the receptor activities prevent ADDL removal and promote its further aggregation. These results provide compelling evidence linking insulin resistance to A␤ abnormality, strongly supporting the hypothesis that dysfunctional CNS insulin or IGF-1 signaling may significantly contribute to the onset and progression of AD pathology (40,41,61,62,85,86).…”

Acceleration of Visual System Development by Environmental Enrichment

“…However, it is known that enriched environment in the adult increases the expression of other factors that are potentially important for visual system development (neurotrophins, signal transduction molecules, NMDA receptors, GAD 65, CREB, and many others) (Molteni et al, 2002) and, in particular, increases IGF-I expression (Carro et al, 2000;Thoenen and Sendtner, 2002). IGF-I receptors are present in the occipital cortex (Frolich et al, 1998), and IGF-I could therefore influence the expression of molecules relevant for visual cortical plasticity such as nerve growth factor and BDNF itself. We are aware of the complexity of the cellular and molecular changes potentially induced by enriched environment in the developing visual cortex.…”

Aging and Alzheimer’s disease: Comparison and associations from molecular to system level

“…Recent work has begun to uncover the underlying mechanisms of insulin signaling dysfunction in AD. Clinically, there is a higher density of insulin receptors in the brain of patients with AD compared to control subjects, possibly reflecting upregulation of the receptor in an attempt to compensate for the decreased functionality of insulin (Frolich et al, 1998). By contrast, some studies reported decreased insulin receptor binding in individuals with AD in comparison with age‐matched control (Arnold et al, 2018; Rivera et al, 2005; Steen et al, 2005).…”