Treatments targeted to enhance brain neurotrophic factor signaling may improve memory functions

Treatments targeted to enhance brain neurotrophic factor signaling could improve memory functions in Alzheimer's disease even though they don't alter brain amyloid burden, according to recent research from the University of Eastern Finland. The enhancement of brain derived neurotrophic factor (BDNF) signaling alleviated memory impairment in Alzheimer's mouse models. In addition, the administration of cerebral dopamine neurotrophic factor (CDNF) into brain tissue improved long-term memory in particular.

Alzheimer' disease is the most common cause of dementia, characterized by the accumulation of amyloid beta peptide in the brain, and so far without a cure. As treatments aimed at reducing amyloid deposits have proved unsuccessful, other treatment approaches are needed. Brain neurotrophic factors offer one potential approach.

Neurons communicate with each other via synaptic connections. Impaired synaptic activity and synapse loss have been reported in Alzheimer's disease, and synapse loss has been shown to correlate with the severity of memory impairment.

Reduced levels of BDNF, the most important neurotrophic factor affecting synaptic function, have also been linked to Alzheimer's disease and cognitive impairment in humans. Hence, the researchers considered it worthwhile to investigate how alterations in BDNF signaling affect memory functions and brain pathology.

Using transgenic APP/PS1 mouse models of Alzheimer's disease with altered BDNF signaling, the research group showed that memory impairment was aggravated by reduced BDNF signaling and alleviated by enhanced BDNF signaling.

Another focus of interest was the potential of CDNF in the treatment of Alzheimer's disease. CDNF has shown strong neuroprotective and even restorative properties in animal models of Parkinson's disease as well as spinal and peripheral nerve injuries. However, its therapeutic effect has not been previously studied in Alzheimer's disease. In this study, CDNF was infused as a pure protein or in a viral vector directly into brain hippocampus. The treatment was shown to improve long-term memory performance of APP/PS1 and wild-type mice.

Both the mice with modifications in BDNF signaling on top of Alzheimer's transgenes and the APP/PS1 mice treated with CDNF underwent an extensive behavioral test battery to measure neurotrophic factor effects on memory functions. The impact on amyloid deposits was studied histologically.

"None of the neurotrophic factor manipulations influenced amyloid deposition, while they all had effects on memory function, also in wild-type mice without amyloid beta pathology," says Susanna Kemppainen, MSc, who presented the results in her doctoral thesis.

"Thus, by enhancing neurotrophic factor signaling it may be possible to improve memory functions without altering brain amyloid burden."



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