Cognitive decline in diabetic mice predisposed to Alzheimer’s disease is greater than in wild type

Abstract

In this work, we tested the hypothesis that the development of dementia in individuals with type 2 diabetes (T2DM) requires a genetic background of predisposition to neurodegenerative disease. As a proof of concept, we induced T2DM in middle-aged hAPP NL/F mice, a preclinical model of Alzheimer’s disease. We show that T2DM produces more severe behavioral, electrophysiological, and structural alterations in these mice compared with wild-type mice. Mechanistically, the deficits are not paralleled by higher levels of toxic forms of Aβ or by neuroinflammation but by a reduction in γ-secretase activity, lower levels of synaptic proteins, and by increased phosphorylation of tau. RNA-seq analysis of the cerebral cortex of hAPP NL/F and wild-type mice suggests that the former could be more susceptible to T2DM because of defects in trans-membrane transport. The results of this work, on the one hand, confirm the importance of the genetic background in the severity of the cognitive disorders in individuals with T2DM and, on the other hand, suggest, among the involved mechanisms, the inhibition of γ-secretase activity.

In vivo retinal imaging is associated with cognitive decline, blood-brain barrier disruption and neuroinflammation in type 2 diabetic mice

“…Concomitant with the changes in retinal thickness, diabetic db/db mice exhibited cognitive decline, with impairments in cortical-hippocampal dependent short-term and hippocampal-amygdala mediated long-term memory tests ( 32 , 33 ). Similar impairments have been published in preclinical diabetes literature ( 4 , 34 , 35 ) using Morris water maze (MWM) and Barnes maze as measures of spatial learning, memory and cognitive flexibility, and y-maze as a marker of working memory ( 33 , 36 ). Cognitive decline in diabetes is supported by neuroimaging data that show altered activity in brain regions involved in cognition ( 8 ).…”

Effect of astaxanthin in type-2 diabetes -induced APPxhQC transgenic and NTG mice

“…Induction of T2D further impaired the memory in NTG mice but not in APPxhQC mice. Variations in the impact of T2D on cognitive function in this study are not outright surprising as reports about the effect of T2D on cognitive performance in experimental animal models have been varying; ranging from increased Aβ deposition due to T2D induction accompanied by memory impairments [ 90 , [100] , [101] , [102] , [103] , [104] ] to no memory impairment or only mild memory dysfunction [ [105] , [106] , [107] ]. Some studies even reported impaired memory function due to T2D induction without increased Aβ deposition [ 108 , 109 ].…”

“…In contrast, in studies using APP/PS1xdb/db mice, increased expression of soluble Aβ 40 and Aβ 42 and reduced deposition of insoluble Aβ 40 and Aβ 42 in the cortex and hippocampus were reported after HFD, connoting a shift in Aβ levels towards more toxic soluble species [ 89 , 113 , 114 ]. Conversely, Carus-Cadavieco and colleagues [ 104 ] reported a reduction in both soluble and insoluble Aβ in streptozocin-HFD-fed hAPP NL/F mice. HFD increased the deposition of insoluble Aβ in hAPP NL/F but not of soluble Aβ [ 90 ].…”