Research Article: Neuroprotective effects of D-Ala2GIP on Alzheimer’s disease biomarkers in an APP/PS1 mouse model

Date Published: April 19, 2013

Publisher: BioMed Central

Author(s): Emilie Faivre, Christian Hölscher.


Type 2 diabetes mellitus has been identified as a risk factor for Alzheimer’s disease (AD). An impairment of insulin signaling as well as a desensitization of its receptor has been found in AD brains. Glucose-dependent insulinotropic polypeptide (GIP) normalises insulin signaling by facilitating insulin release. GIP directly modulates neurotransmitter release, LTP formation, and protects synapses from the detrimental effects of beta-amyloid fragments on LTP formation, and cell proliferation of progenitor cells in the dentate gyrus. Here we investigate the potential therapeutic property of the new long lasting incretin hormone analogue D-Ala2GIP on key symptoms found in a mouse model of Alzheimer’ disease (APPswe/PS1detaE9).

D-Ala2GIP was injected for 21 days at 25 nmol/kg ip once daily in APP/PS1 male mice and wild type (WT) littermates aged 6 or 12 months of age. Amyloid plaque load, inflammation biomarkers, synaptic plasticity in the brain (LTP), and memory were measured.

D-Ala2GIP improved memory in WT mice and rescued the cognitive decline of 12 months old APP/PS1 mice in two different memory tasks. Furthermore, deterioration of synaptic function in the dentate gyrus and cortex was prevented in 12 months old APP/PS1 mice. D-Ala2GIP facilitated synaptic plasticity in APP/PS1 and WT mice and reduced the number of amyloid plaques in the cortex of D-Ala2GIP injected APP/PS1 mice. The inflammatory response in microglia was also reduced.

The results demonstrate that D-Ala2GIP has neuroprotective properties on key hallmarks found in AD. This finding shows that novel GIP analogues have the potential as a novel therapeutic for AD.

Partial Text

Alzheimer’s disease (AD), the most common type of dementia, is a devastating neurodegenerative disorder that has an increasingly high incidence in the elderly. At present, no treatment for AD is known. The disease is officially characterized by two principle hallmarks of pathology, which are amyloid plaques and neurofibrillary tangles (NFTs), composed of aggregated β-amyloid peptide and hyperphosphorylated tau respectively [1-5]. The most prominent feature of AD is the clinical decline in cognitive function, with an early impairment of episodic memory that later manifest as mild cognitive impairment and then later as AD dementia [6,7]. Other biomarkers include inflammation of the brain, loss of cholinergic neurons in the basal brain, glutamatergic neuronal loss, dendritic and synaptic loss among others [8,9].

The current study provides for the first time evidence that chronic administration of D-Ala2GIP can improve cognitive function in WT mice and prevent deficits of learning and memory in APP/PS1 transgenic mice. Body weight, blood glucose and plasma insulin levels were monitored to demonstrate that this drug that had originally had been developed as a treatment for type 2 diabetes does not affect these parameters. Changes in blood glucose and insulin levels would be undesirable and can lead to a deficit in cognitive performance [44,51,52]. APP/PS1 mice had higher body weight at 6 and 12 months old compared to their WT age-matched littermates. At 12 months of age, all mice had a decrease in body weight, which could be the effect of regular exercise during behavioural tasks, increasing energy expenditure and reducing body weight. Higher glucose levels were also found in the APP/PS1 mice at 6 and 12 months old when compared with the WT mice. However, blood glucose levels stayed in a normal range (between 4 and 8 mM/l). Importantly, D-Ala2GIP treatment did not affect body weight, blood glucose levels and plasma insulin levels in either APP/PS1 or WT mice at either of the ages tested. Another important parameter to evaluate was the effect of D-Ala2GIP treatment on the spontaneous behaviour of the transgenic mouse, as a disturbance in locomotor activity, speed or anxiety levels could affect the learning and memory in some behavioural tasks. D-Ala2GIP treatment did not alter locomotor activity measured as path length and number of lines crossed, exploratory levels estimated by the number of rearing events and speed in both transgenic and APP/PS1 mice in all different ages tested. Anxiety levels were assessed by the number of grooming events and the time spent in the centre of the open-field test vs the periphery. Treatment with D-Ala2GIP peptides did not affect the anxiety level of mice. Moreover, spontaneous behaviour was not modified in the open-field task. The same results were found for speed during the acquisition trials in the MWM task. There was also no effect on spontaneous behaviour found previously in C57Bl/6J mice chronically injected with 25 nmol/kg D-Ala2GIP for at least 21 days [43].

In conclusion, the results of chronic administration of D-Ala2GIP demonstrate that GIP analogues have a range of properties that may be beneficial in treating neurodegenerative conditions such as AD. It our study, D-Ala2GIP induced synaptogenesis and protected synapses, which led to cognitive improvement in WT mice and prevented memory decline in APP/PS1 mice. It has been found that GIP also promotes axonal growth after nerve crush [40]. This growth factor-like property can be of use in neuroprotection and neuroregeneration in AD. Moreover, D-Ala2GIP facilitated LTP, highlighting the important role of the GIPR in synaptic plasticity and confirming that synapses were not only protected from degradation in the APP/PS1 mice, but were fully functional. Importantly, D-Ala2GIP decreased the number of amyloid plaques and neuroinflammation in the cortex of transgenic mice. This is of great interest, as neurotoxic effects associated with plaques and inflammation are considered one of the important underlying mechanisms of neurodegeneration found in AD [71,72]. The beneficial actions of GIP suggest that the use of long-lasting analogues may be an attractive therapeutic approach for the treatment of neurodegenerative diseases such as AD. One possible mechanism of action is the re-sensitisation of insulin signaling, or the compensation of insulin de-sensitisation by GIPR activation. Further research in mouse models of neurodegenerative diseases will be required to understand mechanisms that underlie the neuroprotective properties of GIP analogues.

AD: Alzheimer’s disease; ANOVA: analysis of variance; DCC: Dextran-coated charcoal; DCX: doublecortin; DG: dentate gyrus; fEPSPL: field excitatory post-synaptic potential; GABA: gamma amino butyric acid; GIP: glucose-dependent insulinotropic polypeptide; GIPR: GIP receptor; HFS: high-frequency stimulation; HPLC: high performance liquid chromatography; Iba1: ionized calcium binding adaptor molecule 1; ip: intraperitoneally; IR: insulin receptor; KO: knockout; LTP: long-term potentiation; MALDI-TOF: matrix-assisted laser desorption/ionisation time of flight; MWM: Morris water maze; NFT: neurofibrillary tangles; OLT: object location test; ORT: object recognition task; PBS: phosphate-buffered saline; PCR: polymerase chain reaction; PPF: paired-pulse facilitation; RI: recognition index; RIA: radioimmunoassay; WT: wild type.

The work was funded by a grant from the Alzheimer Research UK charity. Dr Holscher is a named inventor of a patent owned by Ulster University that covers the use of GIP analogues for the treatment of neurodegenerative diseases.

EF was a post-graduate student who conducted the research. CH was the supervisor who obtained the funding for the research and wrote the manuscript. Both authors have read and approved the manuscript for publication.




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