Strategies And Molecular Mechanisms Of Endogenous BDNF Treatment In The Alzheimer’s Disease

Alzheimer’s disease（AD）is the leading cause of dementia,and is rapidly becoming one of the most expensive and burdensome diseases in the current century.Current studies suggest that AD is a complex neurodegenerative disease with multiple pathophysiologies.AD is characterized by progressive cognitive impairment,and the pathological features are plaques formed by the deposition of extracellular amyloid β（Aβ）and intracellular neurofibrillary tangles formed by the aggregate of phosphorylated tau protein.Although there are a lot of studies about AD,the current treatments still only improve symptoms and clear Aβ,and there is no effective treatment for the disease.Standard drugs for the treatment of mild to moderate AD:acetylcholinesterase inhibitors and NMDA（N-methyl-D-aspartate）antagonists（Memantine）,which can improve cognitive function.Additionally,some drugs are used to treat mood disorders,agitation,and psychosis associated with advanced AD,as well as monoclonal antibodies that clear Aβ deposits.The therapeutic effect for AD patients is limited.Therefore,it is particularly important to find and explore an effective treatment.Due to the recent failure of drugs to clear Aβ deposits,researchers have turned to other methods.In the early stages of AD patients,entorhinal cortex（EC）is one of the earliest brain regions to experience lesions.Functional magnetic resonance imaging displayed metabolic disturbances in the EC in the early stages of AD.With the aggravation of the disease,the lesion area of the EC spreads to the parietal cortex,which accelerates the pathology.In addition,in the early stages of AD,there is a decline in the number of synapses in the EC,and the synaptic function is disordered.Previous studies found decreased levels of brain-derived neurotrophic factor（BDNF）in the EC of AD patients.Overexpression of BDNF prevents synaptic deficit and improves cognitive function in mouse,rat,and primate AD models,providing a reliable and effective treatment.But the treatment of BDNF still has challenges.Previous studies used exogenous growth factors to treat diseases,but there are problems such as fast metabolism,short half-life,and difficulty in diffusion.Therefore,the method for increasing endogenous BDNF has greater advantages.Using the method of neural tracing,we found paraventricular thalamus（PVT）,the upstream brain region of lateral entorhinal cortex,expressed BDNF,and there were synaptic connections between excitatory neurons in the PVT and neurons in the lateral entorhinal cortex.Since BDNF release is dependent on neuronal activity,we used optogenetics to activate PVT excitatory neurons,and found increased levels of BDNF protein in the lateral entorhinal cortex,suggesting that activation of PVT neurons could release BDNF to the lateral entorhinal cortex.Chronic activation of PVT neurons in 5xFAD（Familial Alzheimer’s Disease,FAD）mice by chemogenetic methods found that chronic activation of PVT excitatory neurons could prevent synaptic loss and alleviate the impairment of social memory in 5xFAD mice,but did not affect the 5xFAD number of neurons.Since the method of increasing endogenous BDNF for the treatment of AD still needs to be explored for clinical application,we hope to find a fast and reliable method.And more evidences show that dietary intervention may be a potential way to improve or treat AD.Ketogenic diet is a low-carbon,high-fat,and moderate-protein diet,and ketone bodies produced in the liver protect neurons.Ketone bodies also enhance cellular mitochondrial function and reduce the expression of inflammatory and apoptotic mediators.Therefore,the ketogenic diet may be a strategy for the treatment of AD.Through cognitive behaviors,we explored the effects of ketogenic diet administration on spatial learning and working memory at different periods of AD.In addition,the effects of ketogenic diet on Aβ plaques,inflammation,neurons,and synapses were also explored.Using the 5xFAD mouse model,we found that the learning ability of 5xFAD mice（AD ketogenic diet group）fed with long-term ketogenic diet（4 months）was significantly stronger than that of 5xFAD fed a normal diet during the behavioral training phase of Barns maze.The learning and memory maintenance ability of 5xFAD mice fed with a standard diet（AD standard diet group）were weaker than that of WT mice fed with standard diet（WT standard diet group）.In T maze test,working memory of the ketogenic diet group was stronger than that of standard diet group.Additionally,we found that the 5xFAD fed with ketogenic diet for short period（2 months）had stronger learning ability and working memory than the 5xFAD mice fed with the standard diet,while there was no difference in memory maintenance between the two groups.However,in the late stage of 5xFAD mice fed with ketogenic diet,the ketogenic diet did not improve the spatial learning and memory abilities of the 5xFAD mice.By immunofluorescence and Golgi staining,we found that ketogenic diet increased the number of synapses in the 5xFAD mice,as well as the number of neurons in the cortex.In addition,the ketogenic diet reduced the number of Aβ plaques in the5 x FAD mice,as well as impaired microglia activity and inflammatory cytokines like interleukin-1β（IL-1β）and tumor necrosis factor-Alpha（tumor necrosis factor-α,TNF-α）protein levels.These results suggest that the ketogenic diet improves AD learning and memory,possibly by decreasing Aβ plaques and attenuating neuroinflammation.Through the intervention of endogenous brain-derived trophic factor and ketogenic diet,we revealed that（1）activation of PVT neurons increased endogenous BDNF expression and synapses in the lateral entorhinal cortex.（2）Ketogenic diet increases the number of neurons and synapses,possibly by reducing Aβ plaques and inhibiting inflammation,and then improves cognitive impairment in AD.This study provides a theoretical basis for AD intervention and mechanism according to studies of neurotrophic factors and diet.