Current and Near-Future Treatment of Alzheimer's Disease

Abstract

Recent findings have improved our understanding of the multifactorial nature of AD. While in early asymptomatic stages of AD, increased amyloid-β synthesis and tau hyperphosphorylation play a key role, while in the latter stages of the disease, numerous dysfunctions of homeostatic mechanisms in neurons, glial cells, and cerebrovascular endothelium determine the rate of progression of clinical symptoms. The main driving forces of advanced neurodegeneration include increased inflammatory reactions in neurons and glial cells, oxidative stress, deficiencies in neurotrophic growth and regenerative capacity of neurons, brain insulin resistance with disturbed metabolism in neurons, or reduction of the activity of the Wnt-β catenin pathway, which should integrate the homeostatic mechanisms of brain tissue. In order to more effectively inhibit the progress of neurodegeneration, combination therapies consisting of drugs that rectify several above-mentioned dysfunctions should be used. It should be noted that many widely-used drugs from various pharmacological groups, "in addition" to the main therapeutic indications, have a beneficial effect on neurodegeneration and may be introduced into clinical practice in combination therapy of AD. There is hope that complex treatment will effectively inhibit the progression of AD and turn it into a slowly progressing chronic disease. Moreover, as the mechanisms of bidirectional communication between the brain and microbiota are better understood, it is expected that these pathways will be harnessed to provide novel methods to enhance health and treat AD.

Keywords: Alzheimer’s disease; Wnt-β catenin pathway; brain insulin resistance; combination therapy; inflammation; oxidative stress.

Fig. (1)

Major factors and intracellular pathways involved in the progression of Alzheimer's disease. At the present stage of knowledge about the pathomechanism of AD, it can be assumed that an important role in driving the pathomechanism of this disease is played by: 1 / high level of inflammation in the brain tissue along with oxidative stress, 2 / deficits in growth signaling pathways and neuroprotective factors, and 3 / reduced Wnt pathway / catenin, which integrates multiple pathways of neuron-glia interaction. The above three dysfunctions can be seen as a junction between many elements of the molecular pathomechanism of AD and are mainly responsible for disease progression. Therefore, any future therapeutic strategies for AD must also effectively reduce the level of inflammatory responses in brain tissue, improve neuronal signaling by growth factors, and enhance Wnt-catenin activity to near-physiological levels.

Fig. (2)

Activation of the Wnt-β catenin pathway. Drugs that activate the Wnt-β catenin pathway will meet the criteria of multitargeted drugs for treatment of neurodegeneration.