Are we close to finding new therapies to slow the course of Alzheimer’s?
The goal of a recent study is to understand which cells are affected in the early stages of Alzheimer’s disease, so as to develop therapeutics that slow down their course.
Neuroscientists specializing in stem cells from the University of Lund in Sweden have developed a research model that allows you to study neurons in the human hippocampus, the brain cells primarily affected by Alzheimer’s disease. The study was published in the Stem Cell Reports journal (Pomeshchik et al., 2020).
In Alzheimer’s disease, the hippocampus, a brain structure that regulates motivation, emotion, learning and memory, is severely affected. However, due to the impossibility of analyzing hippocampal tissue, unless it is post mortem, it is not possible for researchers to understand what are the primordial events that lead to cellular dysfunction and consequent neuronal damage in the patient. The goal for the researchers in question is to understand which cells are affected in the early stages of Alzheimer’s disease, so as to develop therapeutics that slow down their course. Lund researchers managed to generate 3D structures similar to hippocampal tissues, starting from induced pluripotent stem cells (iPSC), called hippocampal spheroids (HS).
In most vertebrate species, including humans, new granular neurons are generated throughout life through a process called neurogenesis and are believed to contribute to memory formation. The new method developed by scientists will increase hippocampal neuron production to study human neurogenesis and, above all, examine how hippocampal cells, including granular neurons and support glia, are altered in the early stages of the disease . In fact, through this methodology they are able to generate young brain cells and examine the first pathogenic changes so as to obtain valuable information on the development and progression of brain diseases (Pomeshchik et al., 2020).
The researchers also used HS to examine cellular dysfunction in Alzheimer’s disease and, more precisely, how cellular pathogenesis differed among individuals. They generated HS from patients with extreme symptoms – a typical Alzheimer’s patient with a mutation in the amyloid precursor protein gene and an atypical individual with a rare mutation in the presenilin 1 gene and subsequently examined cell pathology.
Interestingly, although they exhibited some important common characteristics, the HS of the two mutated genes differed in many other characteristics, which somehow reflected the severity of their symptoms (Pomeshchik et al., 2020).
HS can be used to understand how hippocampal cells are generated and mature over time. They can also be used to examine whether neurogenesis is affected in HS generated by patients with hippocampal lesions compared to control subjects. HS analysis can reveal which cellular dysfunctions occur early in the disease and whether they are identical or different among patients with familiar or idiopathic forms, they can also be used to develop tailor-made treatments for patient subgroups and to understand why some treatments they may or may not be useful (Pomeshchik et al., 2020).
Hippocampal spheroids were recently used to examine the effect of a gene called NeuroD1, the viral expression mediated by NeuroD1 was sufficient to increase the level of synaptic genes, the levels of which are influenced by Alzheimer’s disease, the researchers say improving synaptic transmission will be the key to solving impaired cognition in Alzheimer’s disease (Pomeshchik et al., 2020).