Neuroprotective effects of the amylin analogue pramlintide on Alzheimer's disease pathogenesis and cognition.
Amylin is a metabolic peptide hormone that is co-secreted with insulin from beta cells in the pancreas and activates many of the downstream targets of insulin. To investigate the relationship between this hormone and Alzheimer's disease (AD), we measured plasma human amylin levels in 206 subjects with AD, 64 subjects with mild cognitive impairment, and 111 subjects with no cognitive impairment and found significantly lower amylin levels among subjects with AD and mild cognitive impairment compared with the cognitively intact subjects. To investigate mechanisms underlying amylin's effects in the brain, we administered chronic infusions of the amylin analog pramlintide in the senescence-accelerated prone mouse, a mouse model of sporadic AD. Pramlintide administration improved performance in the novel object recognition task, a validated test of memory and cognition. The pramlintide-treated mice had increased expression of the synaptic marker synapsin I and the kinase cyclin-dependent kinase-5 in the hippocampus, as well as decreased oxidative stress and inflammatory markers in the hippocampus. A dose-dependent increase in cyclin-dependent kinase-5 and activation of extracellular-signal-regulated-kinases 1/2 by pramlintide treatment in vitro was also present indicating functionality of the amylin receptor in neurons. Together these results suggest that amylin analogs have neuroprotective properties and might be of therapeutic benefit in AD.
Department of Neurosciences, Case Western Reserve University, Cleveland OH USA.
Brittany L
BL
Adler
Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, Institute on Aging, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
Mark
M
Yarchoan
Department of Neurosciences, Case Western Reserve University, Cleveland OH USA.
Hae Min
HM
Hwang
Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, Institute on Aging, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
Natalia
N
Louneva
Department of Neurosciences, Case Western Reserve University, Cleveland OH USA.
Jeffrey A
JA
Blair
Department of Neurosciences, Case Western Reserve University, Cleveland OH USA.
Russell
R
Palm
Department of Pathology, Case Western Reserve University, Cleveland OH USA.
Mark A
MA
Smith
Department of Pathology, Case Western Reserve University, Cleveland OH USA.
Hyoung-Gon
HG
Lee
Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, Institute on Aging, University of Pennsylvania School of Medicine, Philadelphia, PA, USA. Electronic address: steven.arnold@uphs.upenn.edu.
Steven E
SE
Arnold
Department of Neurosciences, Case Western Reserve University, Cleveland OH USA. Electronic address: gxc40@case.edu.
Gemma
G
Casadesus
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism / Q000523:psychology*; D000818:Animals; D002478:Cells, Cultured; D003071:Cognition / Q000187:drug effects*; D051360:Cyclin-Dependent Kinase 5 / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D058228:Islet Amyloid Polypeptide / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use*; D008297:Male; D008568:Memory / Q000187:drug effects; D051379:Mice; D008875:Middle Aged; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D018696:Neuroprotective Agents; D018384:Oxidative Stress; D058287:Receptors, Islet Amyloid Polypeptide / Q000378:metabolism; D016704:Synapsins / Q000378:metabolism
D007004:Hypoglycemic Agents; D058228:Islet Amyloid Polypeptide; D018696:Neuroprotective Agents; D058287:Receptors, Islet Amyloid Polypeptide; D016704:Synapsins; C105254:pramlintide; D051360:Cyclin-Dependent Kinase 5; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3
Alzheimer's disease; Amylin; CDK5; Diabetes; IAPP; Incretin; Insulin; Pramlintide; SAMP8; Synaptic plasticity