Abstract
Recent data suggest that olfactory deficits could represent an early marker and a pathogenic mechanism at the basis of cognitive decline in type 2 diabetes (T2D). However, research is needed to further characterize olfactory deficits in diabetes, their relation to cognitive decline and underlying mechanisms.The aim of this study was to determine whether T2D impairs odour detection, olfactory memory as well as neuroplasticity in two major brain areas responsible for olfaction and odour coding: the main olfactory bulb (MOB) and the piriform cortex (PC), respectively. Dipeptidyl peptidase-4 inhibitors (DPP-4i) are clinically used T2D drugs exerting also beneficial effects in the brain. Therefore, we aimed to determine whether DPP-4i could reverse the potentially detrimental effects of T2D on the olfactory system.Non-diabetic Wistar and T2D Goto-Kakizaki rats, untreated or treated for 16 weeks with the DPP-4i linagliptin, were employed. Odour detection and olfactory memory were assessed by using the block, the habituation-dishabituation and the buried pellet tests. We assessed neuroplasticity in the MOB by quantifying adult neurogenesis and GABAergic inhibitory interneurons positive for calbindin, parvalbumin and carletinin. In the PC, neuroplasticity was assessed by quantifying the same populations of interneurons and a newly identified form of olfactory neuroplasticity mediated by post-mitotic doublecortin (DCX) + immature neurons.We show that T2D dramatically reduced odour detection and olfactory memory. Moreover, T2D decreased neurogenesis in the MOB, impaired the differentiation of DCX+ immature neurons in the PC and altered GABAergic interneurons protein expression in both olfactory areas. DPP-4i did not improve odour detection and olfactory memory. However, it normalized T2D-induced effects on neuroplasticity.The results provide new knowledge on the detrimental effects of T2D on the olfactory system. This knowledge could constitute essentials for understanding the interplay between T2D and cognitive decline and for designing effective preventive therapies.
Highlights
Cognitive decline, dementia and Alzheimer’s disease (AD) are often preceded by olfactory deficits [reviewed in [18, 20]]
To determine whether type 2 diabetic (T2D) impairs the neuroplasticity in the olfactory system, we investigated whether GABAergic inhibitory interneurons and adult neurogenesis in the main olfactory bulb (MOB) as well as GABAergic interneurons and the immature DCX+ neurons in the piriform cortex (PC) are affected by T2D
Dipeptidyl peptidase 4 (DPP-4) inhibition normalizes CB+ interneurons in the PC of T2D rats In the PC, the results showed over 40% increase in the number of CB+ interneurons after chronic linagliptin treatment compared to the control group (1849 ± 124 versus 1278 ± 86 cells, p = 0.002) (Fig. 7a-c) suggesting a significant role of Dipeptidyl peptidase-4 inhibitors (DPP-4i) in the regulation of neuroplasticity driven by these cells in the PC
Summary
Dementia and Alzheimer’s disease (AD) are often preceded by olfactory deficits [reviewed in [18, 20]]. Since there is a strong association between T2D and different forms of cognitive decline and dementia, including AD [6, 14, 40, 42, 90], olfactory dysfunction in T2D could represent an early indicator and perhaps even one of the pathogenic mechanisms at the base of future cognitive impairment. Other studies could not detect olfactory deficits in diabetes [2, 9, 71] and these discrepancies call for further investigation. The potential impairment of cognitive functions related to olfaction (e.g olfactory memory) needs to be studied in T2D, since the disruption of these functions in non-diabetics has been associated with aging and cognitive decline [12, 13, 50, 75, 85, 92]
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