Brain microvascular injury and white matter disease provoked by diabetes‐associated hyperamylinemia

Abstract

Objectives The brain blood vessels of patients with type-2 diabetes and dementia have deposition of amylin, an amyloidogenic hormone co-secreted with insulin. It is not known whether vascular amylin deposition is a consequence or a trigger of vascular injury. We tested the hypothesis that the vascular amylin deposits cause endothelial dysfunction and microvascular injury and are modulated by the amylin transport in the brain via plasma apolipoproteins. Methods Rats overexpressing amyloidogenic (human) amylin in the pancreas (HIP rats) and amylin knockout (AKO) rats intravenously infused with aggregated amylin were used for in vivo phenotyping. We also carried out biochemical analyses of human brain tissues and studied the effects of the aggregated amylin on endothelial cells, ex vivo. Results Amylin deposition in brain blood vessels is associated with vessel wall disruption and abnormal surrounding neuropil in patients with type-2 diabetes and dementia, in HIP rats, and in AKO rats infused with aggregated amylin. HIP rats have brain microhemorrhages, white matter injury and neurologic deficits. Vascular amylin deposition provokes loss of endothelial cell coverage and tight junctions. Intravenous infusion in AKO rats of human amylin, or combined human amylin and apolipoprotein E4, showed that amylin binds to plasma apolipoproteins. The intravenous infusion of apolipoprotein E4 exacerbated the brain accumulation of aggregated amylin and vascular pathology in HIP rats. Interpretation These data identify vascular amylin deposition as a trigger of brain endothelial dysfunction that is modulated by plasma apolipoproteins and represents a potential therapeutic target in diabetes-associated dementia and stroke.

Amylin as a Potential Link between Type 2 Diabetes and Alzheimer Disease

“…They noted pancreatic amylin‐Aβ and amylin‐tau deposits in humans with AD in the absence of type 2 diabetes, which the authors interpreted as potential evidence for a role of Aβ and tau tangle pathology in insulin resistance in these subjects. We suggest an alternative interpretation of this finding that we base on 4 key observations: (1) pancreatic β cells express and process both the Aβ protein precursor and tau mRNAs, implying that amylin‐Aβ and amylin‐tau inclusions may originate from the pancreas; (2) affected age‐groups and clinical trajectories in type 2 diabetes and late onset AD generally indicate that diabetes most commonly precedes AD and is associated with an acceleration of the transition from mild cognitive impairment to dementia; (3) consistent with this observation and because rodent amylin is nonamyloidogenic, rodent AD models do not develop type 2 diabetes, whereas pancreatic expression of amyloid‐forming human amylin in non‐AD rats causes type 2 diabetes, brain amylin deposition, and behavior deficits; and (4) the brain region involved in the central regulation of pancreatic β‐cell function (ie, the hypothalamus) is affected by AD pathology. Consequently, AD may impair central signaling pathways that regulate amylin secretion, leading to pancreatic β‐cell dysfunction and impaired clearance of amylin, Aβ, and tau.…”

Review: Relationship of type 2 diabetes to human brain pathology

“…Another study also found deleterious microvascular effects of hyperamylinaemia, finding disruption of vascular wall integrity with associated IAPP deposition in the smooth muscle and arterioles of capillaries of patients with T2D and dementia . Animal models included in the same study demonstrated more microhaemorrhages, white matter injury, and cognitive deficits in animals infused with IAPP or engineered to overproduce the protein . A SNP in IAPP was demonstrated to interact with degree of PET‐imaged cortical amyloid burden, showing a significant association with decreased temporal lobe cortical thickness and cognitive decline .…”

Type 2 Diabetes Mellitus Increases The Risk of Late-Onset Alzheimer’s Disease: Ultrastructural Remodeling of the Neurovascular Unit and Diabetic Gliopathy

“…The following two additional emerging hypotheses may be 'game changers' in regard to both the novel treatments of LOAD by repurposing insulin and insulin sensitizing medication and aiding in the understanding of the development and/or the continuum of progression in LOAD. Aα independent deposition in the perivascular regions and extracellular matrix, which may possibly interfere with Aβ efflux or clearance [169,170,171,172,173,174]. The amylin hypothesis involving the amyloidogenic Aα might also lead to the use of an amylin analog (pramlintide) for clinical study that has already been approved and utilized to treat type 1 and T2DM and known to improve glucose levels [175].…”