Adipose and leptomeningeal arteriole endothelial dysfunction induced by β-amyloid peptide: A practical human model to study Alzheimer's disease vasculopathy

Abstract

Background Evidence point to vascular dysfunction and hypoperfusion as early abnormalities in Alzheimer's disease (AD); probing their mechanistic bases can lead to new therapeutic approaches. We tested the hypotheses that β-amyloid peptide induces endothelial dysfunction and oxidative stress in human microvasculature and that response will be similar between peripheral adipose and brain leptomeningeal arterioles. New Method Abdominal subcutaneous arterioles from living human subjects (n=17) and cadaver leptomeningeal arterioles (n=6) from rapid autopsy were exposed to Aβ1-42 (Aβ) for 1-hour and dilation response to acetylcholine/papaverine were measured and compared to baseline response. Adipose arteriole reactive oxygen species (ROS) production and nitrotyrosine content were measured. Comparison with existing methods Methods described allow direct investigation of human microvessel functional response that cannot be replicated by human noninvasive imaging or post-mortem histology. Results Adipose arterioles exposed to 2 μM Aβ showed impaired dilation to acetylcholine that was reversed by antioxidant polyethylene glycol superoxide dismutase (PEG-SOD) (Aβ-60.9±6%, control-93.2±1.8%, Aβ+PEGSOD-84.7±3.9%, both p<0.05 vs. Aβ). Aβ caused reduced dilation to papaverine. Aβ increased adipose arteriole ROS production and increased arteriole nitrotyrosine content. Leptomeningeal arterioles showed similar impaired response to acetylcholine when exposed to Aβ (43.0±6.2% versus 81.1±5.7% control, p<0.05). Conclusion Aβ exposure induced adipose arteriole endothelial and non-endothelial dysfunction and oxidative stress that were reversed by antioxidant treatment. Aβ-induced endothelial dysfunction was similar between peripheral adipose and leptomeningeal arterioles. Ex vivo living adipose and cadaver leptomeningeal arterioles are viable, novel and practical human tissue models to study Alzheimer's vascular pathophysiology.

Nanoliposomes protect against human arteriole endothelial dysfunction induced by β-amyloid peptide

“…2 Recently, we showed that ex-vivo human leptomeningeal arterioles acutely exposed to soluble b-amyloid peptide 1-42 (Ab42), a major peptide implicated in AD, demonstrate endothelial dysfunction, and that this effect was similar in human abdominal subcutaneous adipose arterioles. 3 We showed similar induction of human arteriole endothelial dysfunction with exposure to light chain proteins derived from patients with AL amyloidosis, [4][5][6] suggesting common vascular toxicity among amyloidogenic proteins despite differences in amino acid composition. When nanoliposomes of less than 100 nM size composed of phospholipids phosphatidylcholine, cholesterol and phosphatidic acid (NLPA) were cotreated with amyloidogenic light chains, endothelial dysfunction was reversed and the b-sheet structure of the light chain protein was altered.…”

“…15 Endothelial dysfunction and cerebral hypoperfusion led to loss of spatial memory even before Ab amyloid accumulation in rat hippocampus. 16 Other investigators and our group showed that Ab caused cerebrovascular endothelial dysfunction in both transgenic mouse models and human tissues 3,17 pointing to its potential role in chronic ischemic brain injury in AD. Reversing the adverse effects of Ab on human microvascular endothelial function may represent an important early therapeutic approach.…”

“…The dose of Ab42 was chosen because this is less than but close to the reported concentration ($30,000 ng/g tissue) found in cortical tissue of patients with AD. 3,12 The dose of NLPA was chosen because this was similar to the dose that restored endothelial function in adipose arterioles exposed to AL amyloid light chain proteins. 7 In additional arterioles, Ab42 and NLPA were co-treated with L-NG-nitroarginine methyl ester (L-NAME, 5 mmol), an inhibitor of nitric oxide (NO) synthase (NOS).…”

“…Some of the data on leptomeningeal arteriole response to Ab42 (n ¼ 4) were reported in the same previous study 3 with additional replicates (n ¼ 10) added for this manuscript.…”

Adipobiology of the brain: From brain diabetes to adipose Alzheimer‘s disease

“…Indeed, obesity, diabetes and/or metabolic syndrome may a ect multiple cognitive functions including expression of APP, amyloid-β (Aβ) peptide and tau hyperphosphorylation -molecular signatures of AD pathology. In brief, an extraneuronal production of both APP and Aβ peptides including the adipose tissue was demonstrated (25)(26)(27)(28)(29)(30). Accordingly, the administration of streptozotocin (STZ), a well known experimental model for diabetes, induces brain insulin resistance and cognitive alterations resembling those in AD patients (31)(32)(33).…”