Summary: Researchers report a drug used to treat diabetes may be successful at treating Alzheimer’s disease also.

Source: University of Aberdeen.

Drugs used to treat diabetes could also be used to treat Alzheimer’s disease, and vice versa, according to new research from the University.

This is also the first study of its kind to show that Alzheimer’s disease can lead to diabetes, as opposed to diabetes occurring first as was previously thought.

The study reports that Alzheimer’s Disease and type 2 diabetes are so closely related that drugs currently used to control glucose levels in diabetes may also alleviate the symptoms and progression of Alzheimer’s disease.

The paper, published in the journal Diabetologia, found for the first time that dementia-related complications within the brain can also lead to changes in glucose handling and ultimately diabetes. This is contrary to what was previously thought – that diabetes begins with a malfunction in the pancreas or a high fat, high sugar diet.

The research was led by Professor Bettina Platt who formed a unique collaboration between her Alzheimer’s research team and the diabetes research team led by Professor Mirela Delibegovic. The teams were keen to investigate why the two diseases are so commonly found together in elderly patients.

The researchers developed a model of Alzheimer’s disease and were surprised to find that increased levels of a gene involved in the production of toxic proteins in the brain not only led to Alzheimer’s -like symptoms, but also to the development of diabetic complications.

Professor Platt said of her research: “Many people are unaware of the relationship between diabetes and Alzheimer’s disease, but the fact is that around 80% of people with Alzheimer’s disease also have some form of diabetes or disturbed glucose metabolism. This is hugely relevant as Alzheimer’s is in the vast majority of cases not inherited, and lifestyle factors and comorbidities must therefore be to blame.

“Our research teams are particularly interested in the impact of lifestyle related factors in dementia and by collaborating with experts in diabetes and metabolism, we have been able to investigate the nature of the link in great detail.

“Until now, we always assumed that obese people get type 2 diabetes and then are more likely to get dementia – we now show that actually it also works the other way around.

blue brain

“Additionally, it was previously believed that diabetes starts in the periphery, i.e. the pancreas and liver, often due to consumption of an unhealthy diet, but here we show that dysregulation in the brain can equally lead to development of very severe diabetes – so again showing that diabetes doesn’t necessarily have to start with your body getting fat – it can start with changes in the brain.

“This study provides a new therapeutic angle into Alzheimer’s disease and we now think that some of the compounds that are used for obesity and diabetic deregulation might potentially be beneficial for Alzheimer’s patients as well. The good news is that there are a number of new drugs available right now which we are testing to see if they would reverse both Alzheimer’s and diabetes symptoms. We will also be able to study whether new treatments developed for Alzheimer’s can improve both, the diabetic and cognitive symptoms.”

ABOUT THIS ALZHEIMER’S DISEASE ARTICLE

Finding: The research was funded by R, Simcox, Romex Oilfield Chemicals, the Scottish Alzheimer’s Research UK network, British Heart Foundation, Diabetes UK and European Foundation for the Study of Diabetes/Lilly programme grant.

Source: Wendy Skene – University of Aberdeen
Image Source: This NeuroscienceNews.com image is adapted from the University of Aberdeen press release.
Original Research: Full open access research for “Neuronal human BACE1 knockin induces systemic diabetes in mice” by Kaja Plucińska, Ruta Dekeryte, David Koss, Kirsty Shearer, Nimesh Mody, Phillip D. Whitfield, Mary K. Doherty, Marco Mingarelli, Andy Welch, Gernot Riedel, Mirela Delibegovic, and Bettina Platt in Diabetologia. Published online May 2 2016 doi:10.1007/s00125-016-3960-1

University of Aberdeen. “New Link Found Between Diabetes and Alzheimer’s.” NeuroscienceNews. NeuroscienceNews, 21 June 2016.
<http://neurosciencenews.com/diabetes-alzheimers-neurology-4531/&gt;.

Abstract

Neuronal human BACE1 knockin induces systemic diabetes in mice

Aims

β-Secretase 1 (BACE1) is a key enzyme in Alzheimer’s disease pathogenesis that catalyses the amyloidogenic cleavage of amyloid precursor protein (APP). Recently, global Bace1 deletion was shown to protect against diet-induced obesity and diabetes, suggesting that BACE1 is a potential regulator of glucose homeostasis. Here, we investigated whether increased neuronal BACE1 is sufficient to alter systemic glucose metabolism, using a neuron-specific human BACE1 knockin mouse model (PLB4).

Methods

Glucose homeostasis and adiposity were determined by glucose tolerance tests and EchoMRI, lipid species were measured by quantitative lipidomics, and biochemical and molecular alterations were assessed by western blotting, quantitative PCR and ELISAs. Glucose uptake in the brain and upper body was measured via 18FDG-PET imaging.

Results

Physiological and molecular analyses demonstrated that centrally expressed human BACE1 induced systemic glucose intolerance in mice from 4 months of age onward, alongside a fatty liver phenotype and impaired hepatic glycogen storage. This diabetic phenotype was associated with hypothalamic pathology, i.e. deregulation of the melanocortin system, and advanced endoplasmic reticulum (ER) stress indicated by elevated central C/EBP homologous protein (CHOP) signalling and hyperphosphorylation of its regulator eukaryotic translation initiation factor 2α (eIF2α). In vivo 18FDG-PET imaging further confirmed brain glucose hypometabolism in these mice; this corresponded with altered neuronal insulin-related signalling, enhanced protein tyrosine phosphatase 1B (PTP1B) and retinol-binding protein 4 (RBP4) levels, along with upregulation of the ribosomal protein and lipid translation machinery. Increased forebrain and plasma lipid accumulation (i.e. ceramides, triacylglycerols, phospholipids) was identified via lipidomics analysis.

Conclusions/interpretation

Our data reveal that neuronal BACE1 is a key regulator of metabolic homeostasis and provide a potential mechanism for the high prevalence of metabolic disturbance in Alzheimer’s disease.

“Neuronal human BACE1 knockin induces systemic diabetes in mice” by Kaja Plucińska, Ruta Dekeryte, David Koss, Kirsty Shearer, Nimesh Mody, Phillip D. Whitfield, Mary K. Doherty, Marco Mingarelli, Andy Welch, Gernot Riedel, Mirela Delibegovic, and Bettina Platt in Diabetologia. Published online May 2 2016 doi:10.1007/s00125-016-3960-1