Warning signs in the brains of Alzheimer's disease patients

In Alzheimer’s disease, pathophysiological changes occur years before the onset of the first cognitive deficits. Progressive alterations in Notch1 protein affect synaptic plasticity and can contribute to memory loss. The group of Dr. Alberi at the Department of Medicine of the University of Fribourg seeks to understand whether Notch1 can be considered as a novel Biomarker in the early diagnosis of Alzheimer’s disease.

In the brain of demented patients, Notch1 co-localizes with p-Tau in fibrillary plaques labeled by Thioflavin-T (white arrows), whereas in the healthy controls there is no presence of aberrant aggregates.

Alzheimer’s is a neurodegenerative disease characterized by neuronal death, appearance of senile plaques in the brain, loss of memory and dementia. Nowadays, in Europe there are about 6 Million people affected by dementia and in Switzerland there are 119’000 Alzheimer’s patients, about the population of the city of Bern. The disease progresses through specific stages, which can span more than 20 years involving the spread of neurofibrillary tangles and amyloid plaques. Interestingly, the appearance of neurofibrillary tangles and plaques begins much earlier than the symptoms. Experiments in rodents show that neither blocking amyloid plaques deposition nor neurofibrillary tangles formation can complete rescue memory, thus additional molecular targets need to be identified in order to develop effective therapeutical strategies against this devastating disease.

Potential for a new Biomarker in Alzheimer’s disease

Neurons are connected through synapses. The most important region of the brain for memory formation is the hippocampus. In Alzheimer’s disease, the most common form of dementia, hippocampal connections are progressively weakened and information is not properly processed and stored. As a consequence, patients suffer from memory impairment and disorientation. The group of Dr. Alberi at the Department of Medicine of the University of Fribourg investigates the biological role of Notch1 signaling in memory and neurodegeneration. In the recently published manuscript, in the journal Acta Neuropathologica Communications, Dr. Alberi’s group performed a detailed mapping of Notch1 alterations in post-mortem brains of Alzheimer’s patients. The first author of the study, Dr. Emanuele Brai, observed a dramatic displacement of the signaling molecule, Notch1, from the neurons to tangles and plaques suggesting a critical role of Notch1 in the synaptic impairment and associated dementia. Alterations in Notch1 are detectable also in the cerebrospinal fluid suggesting that Notch1 may be also used as early diagnostic biomarker. “If we can detect the disease early enough, we have better chances in developing more effective therapies to halt the progression of dementia, and maybe, one day, even revert the symptoms” commented Dr. Lavinia Alberi.

This paper presents important findings regarding the involvement of Notch1 in Alzheimer’s disease pathophysiology and opens new avenues for further preclinical and clinical research to finally address whether Notch1 can be therapeutically targeted and used as a novel biomarker for Alzheimer’s disease. To pursue such translational research, Dr. Alberi’s group is relocating to the newly established Swiss Integrative Center for Human Health as Lead of Neurology Research. The planned studies will be carried out in collaboration with the Clinical Neurology of the Cantonal Hospital of Fribourg and the Chair of Pathology of the University of Fribourg.

The study was supported by the Swiss National Foundation for Science (SNF) and the Synapsis Foundation for Alzheimer’s Research Switzerland.


Website SICHH

Publication on Acta Neuropathologica Communications

Publication on NCBI