In Alzheimer’s disease (AD), we are gaining great ground in the field of early diagnosis, but disease-modifying drugs are still missing. While many studies have been focused on the pathogenic role of amyloid-β (Aβ) dysmetabolism, recent preclinical and clinical findings revealed a more complex picture. In AD, we need to embrace a complex view of the disease state as a condition resulting from the converging failure of health-controlling systems and networks; A condition shaped by the combination of our “omic” blueprint and the influence of the environment. AD is, in fact, a multifactorial condition in which, along with Aβ accumulation, the convergence of many genetic, environmental, vascular, metabolic, and inflammatory factors increase the likelihood of developing the disease. All these conditions find fertile ground inside and outside of the central nervous system provided by aging. In that respect, approaches targeting co-morbidity factors are becoming promising as, at least, a third of AD cases are strongly dependent on the concerted activity of modifiable factors (low education, midlife hypertension, midlife obesity, diabetes, physical inactivity, smoking, and depression) [1,2]. One promising area of early intervention concerns the vascular system. Systematic reviews have revealed that cardiovascular factors go out of range in young adulthood or middle age (<65 years), but not necessarily in late life (≥75 years), and studies indicate that such early “early on” alterations are the ones associated with an increased AD risk [3,4].
A very promising area of investigation and intervention is now offered by insulin-related signaling . In the brain, the hormone acts as a neurotrophic factor and critically modulates neuronal survival, synaptic plasticity, and the molecular pathways underlying learning and memory processes . Decreased insulin sensitivity is found upon brain aging, and defective insulin signaling has been reported in subjects affected by mild cognitive impairment and AD patients . An intriguing target of action is now provided by the agonists of the glucagon-like peptide-1 receptor (GLP-1R). Glucagone is an endogenous insulinotropic hormone that participates in the homeostatic regulation of insulin and glucose. Like insulin, the activation of the GLP-1Rs impacts on neuronal excitability, synaptic plasticity, and memory processes [8–11]. These effects are largely obtained through the activation of the cAMP response element-binding protein (CREB), the induction of the expression of the brain-derived neurotrophic factor (BDNF), and the activation of its tropomyosin-related kinase B receptor (TrkB). GLP-1 analogs have been successfully tested in preclinical models of neurodegeneration and in clinical trials. In particular, exenatide, a GLP-1R agonist approved for type 2 diabetes mellitus treatment, is under evaluation in trials targeting AD and was found to produce important beneficial effects in Parkinson’s disease (NCT01255163, NCT01174810, NCT01971242) [12–15].
We have tested a 6-month treatment with exenatide in Presenilin-1 Knock-In (PS1-KI) mice, a preclinical model of amyloid-independent neuronal dysfunction and found that the molecule promotes beneficial effects on short- and long-term memory performances . In a more recent study, we have also found that a 2-month exenatide treatment resulted in enhanced cognitive performances in adult mice. The study is relevant in terms of translational value as the timeframe of intervention (animals at 10-12 month of age) matches the mid-life stage of humans, thereby opening a window of opportunity for preventative intervention in a critical pre-symptomatic phase and may offer the possibility to revert or at least halt the disease progression. In the study, exenatide was found to exert positive effects through the phosphorylation of CREB, that eventually leads to increased expression levels of BDNF and TrkB and downstream activation of BDNF-related signaling .
These results pinpoint to the importance of targeting neurotrophic systems and BDNF in particular. Mature BDNF promotes neurogenesis, neurite outgrowth, dendritic arborization, spine formation, and long-term potentiation, and is crucial for shaping synaptic plasticity and to promote neuroprotection upon adulthood and against AD-related neurodegeneration [18,19]. High levels of brain BDNF expression are associated with decreasing rate of cognitive decline and a milder course of AD [20,21]. BNDF levels are increased by physical activity and represent one of the significant beneficial effects of interventions aimed at promoting healthier lifestyles. Intriguingly, serotonergic psychedelics have also been shown in vitro and in vivo, to promote synaptogenesis and structural plasticity through the activation of BDNF signaling. These findings are thereby prompting the search for new serotoninergic compounds devoid of psychotropic effects and engineered to facilitate BDNF-related signaling . It is also conceivable that more focused efforts aimed at the synthesis of human BDNF or affordable TrkB agonists may promote the therapeutic revolution that occurred in diabetes upon the introduction of human insulin. A mix of new or rediscovered BDNF-modulating drugs, like exenatide or GLP1-R agonists, along with exercise and vascular and metabolic interventions may finally offer the therapeutic options that we have been waited for so long.
Are we finally ready to embrace and pursue an amyloid-independent therapeutic strategy?
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