GDF11 Rejuvenates Cerebrovascular Structure and Function in an Animal Model of Alzheimer’s Disease

Abstract

Cerebral amyloid angiopathy (CAA) is present in up to 90% of patients with Alzheimer's disease (AD), and may interact with classical neuropathology to exacerbate cognitive decline. Since growth differentiation factor 11 (GDF11) can activate vascular remodeling, we tested its effects on cognitive function and neuroinflammatory changes of AD model mice. We intravenously administered GDF11 or vehicle daily to 12-month-old transgenic mice overexpressing the amyloid-β protein precursor (AβPP)/PS1). Cognitive function was monitored using the Morris water maze, and after conclusion of the treatment, we assessed the morphology and presence of inflammatory markers in the cerebral vasculature. Subchronic treatment of adult AβPP/PS1 mice with GDF11 rescued cognitive function and ameliorated cerebrovascular function. In particular, the de novo genesis of small blood vessels and the expression of vascular-related proteins were significantly higher than in the vehicle-treated AβPP/PS1 mice, whereas the expressions of the inflammatory markers Iba-1 and GFAP significantly decreased in proportion to the lower ratio of two forms of amyloid-β (Aβ40/42). Daily intravenous treatment with GDF11-injection can rejuvenate respects of cognition and cerebrovascular changes in AD mice.

Growth Differentiation Factor 11 treatment leads to neuronal and vascular improvements in the hippocampus of aged mice

“…Whether GDF11-treated old mice exhibit improved cognition through olfactory discrimination tasks and/or hippocampus-dependent spatial navigation tasks also needs further research. Notably, recent studies have shown improved neurocognitive behavior in rodents treated with GDF11 in stroke 50 , 53 and AD 52 models. Therefore, it is feasible that systemic GDF11 treatment also could lead to enhanced cognition in aging.…”

Growth differentiation factor 11 ameliorates experimental colitis by inhibiting NLRP3 inflammasome activation

“…One study demonstrates that GDF11 reduces the mRNA levels of IL-6, IL-1␤, and TNF-␣ during atherosclerosis lesion formation in apoE Ϫ/Ϫ mice fed with high-fat diet, together with the protein levels of IL-6 and TNF-␣ (28). Another study reports that GDF11 inhibits the expression of the inflammatory markers Iba-1 and glial fibrillary acidic protein in the cerebral vasculature of Alzheimer's disease mice (46). In this study, we confirmed that GDF11 had Fig.…”

“…Previous studies have shown that restoring systemic GDF11 level reversed age-related cardiac hypertrophy and brain dysfunction (20,23). Recently, studies have reported that both the levels of proinflammatory cytokines in apolipoprotein E-null mice and the neuroinflammatory changes in the brain parenchyma of Alzheimer's disease model mice significantly decreased after GDF11 treatment (28,46). Additionally, UC is a kind of inflammatory disease in the gastrointestinal tract, but there have been no reports on the role of GDF11 in the regulation of intestinal inflammation during UC.…”

Systemic GDF11 stimulates the secretion of adiponectin and induces a calorie restriction‐like phenotype in aged mice

“…Subsequently, other reports argued that GDF11 was positively associated with aging, cachexia, and inhibition of muscle regeneration in aged mice (Egerman et al, ; Harper et al, ; Jones et al, ), while different studies showed a beneficial role for GDF11 in the periphery (Poggioli et al, ; Su et al, ; Walker et al, ). In the central nervous system, GDF11 was also shown to be neuroprotective for neurovascular recovery and neurogenesis (Anqi, Ruiqi, Yanming, & Chao, ; Ma et al, ; Ozek, Krolewski, Buchanan, & Rubin, ; Schafer & LeBrasseur, ; Zhang et al, ).…”