Insulin differentially affects the distribution kinetics of amyloid beta 40 and 42 in plasma and brain

Abstract

Impaired brain clearance of amyloid-beta peptides (Aβ) 40 and 42 across the blood-brain barrier (BBB) is believed to be one of the pathways responsible for Alzheimer's disease (AD) pathogenesis. Hyperinsulinemia prevalent in type II diabetes was shown to damage cerebral vasculature and increase Aβ accumulation in AD brain. However, there is no clarity on how aberrations in peripheral insulin levels affect Aβ accumulation in the brain. This study describes, for the first time, an intricate relation between plasma insulin and Aβ transport at the BBB. Upon peripheral insulin administration in wild-type mice: the plasma clearance of Aβ40 increased, but Aβ42 clearance reduced; the plasma-to-brain influx of Aβ40 increased, and that of Aβ42 reduced; and the clearance of intracerebrally injected Aβ40 decreased, whereas Aβ42 clearance increased. In hCMEC/D3 monolayers (in vitro BBB model) exposed to insulin, the luminal uptake and luminal-to-abluminal permeability of Aβ40 increased and that of Aβ42 reduced; the abluminal-to-luminal permeability of Aβ40 decreased, whereas Aβ42 permeability increased. Moreover, Aβ cellular trafficking machinery was altered. In summary, Aβ40 and Aβ42 demonstrated distinct distribution kinetics in plasma and brain compartments, and insulin differentially modulated their distribution. Cerebrovascular disease and metabolic disorders may disrupt this intricate homeostasis and aggravate AD pathology.

Melatonin and inflammation—Story of a double‐edged blade

“…Whether brain insulin resistance has consequences similar to those in type 2 diabetes, or whether it may represent a separate type of pathology referred to as type 3 diabetes, remains to be a matter of debate. Recently, effects of hyperinsulinemia were reported concerning the clearance of Aβ peptides over the blood‐brain barrier, however, with divergent results in Aβ 1‐40 and Aβ 1‐42 , details that will need further clarification with regard to their pathological consequences. Type 2 diabetes is known to represent a risk for cognitive impairment and dementia .…”

Meta-analysis: Resistance Training Improves Cognition in Mild Cognitive Impairment

“…Additionally, exercise, especially resistance training, may affect the burden of amyloid plaques, which are associated with cognitive decline [16][17][18][19]. One study found that resistance training can directly decrease circulating insulin [20], of which an increase may affect the distribution of amyloid 40 and 42 in brain regions, resulting in the accumulation of amyloid plaques [21,22]. Holten et al note that resistance training increases glucose transporter type 4, insulin receptor, PKB-α/β and glycogen synthase protein content, which indirectly reduces the content of insulin by increasing glucose metabolism and insulin sensitivity and reducing insulin resistance [23].…”

Cognitive dysfunction: A growing link between diabetes and Alzheimer's disease

“…On treatment with insulin, there was reversal of this complication which depicts the role of insulin deficiency behind the development of tau pathology in diabetes (Van der Harg et al, ). Insulin modulated Aβ40 and Aβ42 distribution in mice which reflects dysregulation of insulin in case of metabolic disorder as a possible reason behind altered Aβ level (Swaminathan et al, ).…”

“…Insulin deficiency or insulin resistance is the major etiology behind the development of diabetes. Apart from its role in maintenance of blood glucose, it is also suggested to be involved in AD-like cognitive deficits (Swaminathan et al, 2018).…”