TY - JOUR
T1 - An extended release GLP-1 analogue increases α-synuclein accumulation in a mouse model of prodromal Parkinson's disease
AU - Bergkvist, Liza
AU - Johnson, Michaela E.
AU - Mercado, Gabriela
AU - Steiner, Jennifer A.
AU - Meyerdirk, Lindsay
AU - Schulz, Emily
AU - Madaj, Zachary
AU - Ma, Jiyan
AU - Becker, Katelyn
AU - Li, Yazhou
AU - Brundin, Patrik
PY - 2021/7
Y1 - 2021/7
N2 - The repurposing of drugs developed to treat type 2 diabetes for the treatment of Parkinson's disease (PD) was encouraged by the beneficial effect exerted by the glucagon-like peptide 1 (GLP-1) analogue exenatide in a phase 2 clinical trial. The effects of GLP-1 analogues have been investigated extensively using rodent toxin models of PD. However, many of the toxin-based models used lack robust α-synuclein (α-syn) pathology, akin to the Lewy bodies and neurites seen in PD. One prior study has reported a protective effect of a GLP-1 analogue on midbrain dopamine neurons following injection of α-syn preformed fibrils (PFF) into the striatum. Here, we used olfactory bulb injections of PFF as a model of prodromal PD and monitored the effect of a long-acting GLP-1 analogue on the propagation of α-syn pathology in the olfactory system. Thirteen weeks after PFF injection, mice treated with long-acting the GLP-1 analogue had a significant increase in pathological α-syn in brain regions connected to the olfactory bulb, accompanied by signs of microglia activation. Our results suggest that the nature of the neuronal insult and intrinsic properties of the targeted neuronal population markedly influence the effect of GLP-1 analogues.
AB - The repurposing of drugs developed to treat type 2 diabetes for the treatment of Parkinson's disease (PD) was encouraged by the beneficial effect exerted by the glucagon-like peptide 1 (GLP-1) analogue exenatide in a phase 2 clinical trial. The effects of GLP-1 analogues have been investigated extensively using rodent toxin models of PD. However, many of the toxin-based models used lack robust α-synuclein (α-syn) pathology, akin to the Lewy bodies and neurites seen in PD. One prior study has reported a protective effect of a GLP-1 analogue on midbrain dopamine neurons following injection of α-syn preformed fibrils (PFF) into the striatum. Here, we used olfactory bulb injections of PFF as a model of prodromal PD and monitored the effect of a long-acting GLP-1 analogue on the propagation of α-syn pathology in the olfactory system. Thirteen weeks after PFF injection, mice treated with long-acting the GLP-1 analogue had a significant increase in pathological α-syn in brain regions connected to the olfactory bulb, accompanied by signs of microglia activation. Our results suggest that the nature of the neuronal insult and intrinsic properties of the targeted neuronal population markedly influence the effect of GLP-1 analogues.
KW - Alpha-synuclein
KW - GLP-1 analogue
KW - Parkinson's disease
UR - http://www.scopus.com/inward/record.url?scp=85102791177&partnerID=8YFLogxK
U2 - 10.1016/j.expneurol.2021.113693
DO - 10.1016/j.expneurol.2021.113693
M3 - Article
C2 - 33727096
AN - SCOPUS:85102791177
SN - 0014-4886
VL - 341
JO - Experimental Neurology
JF - Experimental Neurology
M1 - 113693
ER -
