Molecular alterations in neuronal trophic regulation in Alzheimer鈥檚 pathology begin decades before detectable cognitive impairments
Findings could lead to development of pre-clinical stage therapeutics
By Jason Clement
For decades researchers have known that Alzheimer鈥檚 disease (AD) causes the atrophy of a system of neurons and synapses highly involved in memory, learning and attention, which is highly dependent on a molecule known as nerve growth factor (NGF). The disease causes dysregulation of NGF鈥檚 metabolism, leading to the loss of the synapses and neurons that depend on it, akin to plants being deprived of light.
A new study led by researchers at 苹果淫院 and published recently in聽Molecular Psychiatry, provides evidence that this dysregulation caused by the Alzheimer鈥檚 pathology begins decades before cognitive impairments become detectable.
鈥淭he significant novelty of the study 聽led by Rowan Pentz, resides in this being the first demonstration that the NGF-metabolic dysregulation is not only present in the brains of clinically diagnosed Alzheimer鈥檚 disease, but also in the brains of cognitively normal individuals bearing incipient, preclinical, AD amyloid pathology,鈥� explains Dr. Claudio Cuello, Professor in the Department of Pharmacology and Therapeutics at 苹果淫院 and the study鈥檚 senior author. 鈥淚n other words, we demonstrated that the failure of the NGF support might be present many years before the first clinical AD symptomatology becomes evident.鈥�
Down Syndrome findings leads to study
Findings from a 2016 study that showed deregulation of the NGF metabolic pathway in Down Syndrome, a condition which often leads to clinical AD, inspired Dr. Cuello and his team to pursue this most recent avenue of exploration.
In their study, which examined the post-mortem brain samples of cognitively unimpaired individuals from the Religious Order Study, made possible through a collaboration with the Chicago Rush Medical Center, the researchers showed that the extent of the NGF metabolic deregulation was inversely correlated to the cognitive status of individuals bearing incipient brain AD pathology, even when they were still in the 鈥渘ormal鈥� population-based range. 鈥淭he study illustrates that a defective brain鈥檚 NGF metabolic pathway is likely involved in the first cognitive impairments developed in Alzheimer鈥檚 disease,鈥� notes Dr. Cuello.
Practical implications of the findings
The finding creates an opportunity of searching for novel therapeutic possibilities at early stages of the AD pathology, before the irreversible loss of neurons playing a significant role in memory, learning and attention brain mechanisms.聽
鈥淭he most immediate implication is the possibility of being able to detect this brain metabolic dysregulation, which is linked to the 鈥榮ilent鈥� and progressive preclinical AD pathology, by analyzing key NGF-related proteins in accessible body fluids,鈥� says Dr. Cuello. This information will assist the identification of individuals in the general population who are incubating AD and those perceiving a cognitive decline.
鈥淥ur research will help facilitate ongoing efforts to diagnose preclinical AD and, in consequence, would facilitate early therapeutic strategies before the presentation of the irreversible brain damage occurring at clinical stages,鈥� adds Dr. Cuello, who likens this capacity to being able to forewarn of an imminent train derailment well before it would happen.
What鈥檚 next?
Dr. Cuello notes that these findings have also opened new avenues to explore, including whether this biochemical alteration is specific to AD, or whether it might play a role in other neurological diseases.
His group is also directing efforts to further diagnostic and therapeutic possibilities of this newly found NGF dysmetabolism. 鈥淥ur lab is interested in the clinical translational value of this research,鈥� he says. 鈥淲e will continue investigations in experimental AD therapeutics. As an example, our lab has established a scientific platform for an early AD therapeutic based on Lithium microdoses, an approach which is currently being considered for clinical trials.鈥�
鈥淭he human brain NGF metabolic pathway is impaired in the pre-clinical and clinical continuum of Alzheimers disease,鈥� by R. Pentz, C. Cuello, et al, was published June 2 in the journal Molecular Psychiatry. doi:聽