The Dipeptidyl Peptidase-4 Inhibitor Linagliptin Ameliorates High-fat Induced Cognitive Decline in Tauopathy Model Mice

Abstract

Vascular risk factors, such as type 2 diabetes mellitus (T2DM), are associated with the increased risk of Alzheimer’s disease. One of the common T2DM medications, dipeptidyl peptidase (DPP)-4 inhibitors, have a minimum risk for hypoglycemia and have recently been suggested to ameliorate β-amyloid pathology. However, conflicting results have been reported regarding the effects of DPP-4 inhibition on cognitive function and tau pathology. Thus, we investigated whether inhibiting DPP-4 affects tau pathology and cognition in a mouse model of tauopathy with hyperglycemia. Male mice overexpressing the P301S mutant human microtubule-associated protein tau gene (PS19) were fed either a low or high-fat diet. PS19 mice were then administered either linagliptin, a DPP-4 inhibitor, or vehicle, from 6 weeks to 8 months of age. Linagliptin-treated mice exhibited higher levels of glucagon-like peptide-1 and decreased fasting blood glucose, compared with the vehicle-treated mice at 8 months. Linagliptin treatment significantly restored spatial reference memory and increased cerebral blood flow without affecting phosphorylation levels of tau or endothelial nitric oxide synthase (eNOS) in the brain. Linagliptin may ameliorate HFD-induced cognitive worsening in tauopathy, at least partially, by increasing cerebral perfusion via the eNOS-independent pathway.

Liraglutide improved the cognitive function of diabetic mice via the receptor of advanced glycation end products down-regulation

“…GLP-1RA showed obvious neuroprotective effect in neuronal cell lines [ 39 , 40 ], animal models [ 31 , 41 ] with or without diabetes mellitus and diabetic patients [ 42 ]. In this recent study, improved viability of PC12 cells with by AGEs (600μg/ml) at 48h and HT22 cells with by AGEs (400μg/ml) at 72h by liraglutide at a concentration of 200nM or 500nM were measured ( Figures 3F , 4F ).…”

“…Moreover, it can reverse neuronal loss [ 30 ]. Additionally, it was showed that liraglutide improved cognition in non-diabetic individuals [ 31 ]. Owning to blood-brain barrier, large molecules, like semaglutide cannot reach the CNS, but liraglutide as a small molecule, can directly affect neurons in the brain.…”

Relationships between memory decline and the use of metformin or DPP4 inhibitors in people with type 2 diabetes with normal cognition or Alzheimer's disease, and the role APOE carrier status

“…10,[27][28][29][30] The DDP4 inhibitor linagliptin also increased cerebral blood flow in AD mouse models. 31 Generally, the DPP4 inhibitors have been hypothesized to exert beneficial effects on cognition that are related to AD pathological mechanisms. This is consistent with the observed relationship with slower memory decline in patients with AD, and with their significantly larger associations with memory in cognitively normal APOE ε4 carriers, who may have accelerated early AD pathology.…”

“…In animal and cell models, DPP4 inhibitors have been shown to increase hippocampal GLP1 levels, reduce hippocampal Aβ and p‐tau levels, alleviate Aβ plaque formation, and suppress neuroinflammation 10,27–30 . The DDP4 inhibitor linagliptin also increased cerebral blood flow in AD mouse models 31 . Generally, the DPP4 inhibitors have been hypothesized to exert beneficial effects on cognition that are related to AD pathological mechanisms.…”

The dipeptidyl peptidase-4 inhibitor, linagliptin, improves cognitive impairment in streptozotocin-induced diabetic mice by inhibiting oxidative stress and microglial activation

“…A previous study has shown that a DPP-4 inhibitor improved cognitive dysfunction by increasing the GLP-1 concentration in the brain [10,11]. Recently, Nakaoku et al also reported that linagliptin ameliorates high-fat induced cognitive decline in tauopathy model mice [29]. Several studies have demonstrated that GLP-1 alleviated learning and memory dysfunction [30] and that a GLP-1 analogue and GIP analogue prevented memory impairments [31,32].…”