Amelioration of Alzheimer’s disease pathology by mitophagy inducers identified via machine learning and a cross-species workflow

A reduced removal of dysfunctional mitochondria is common to aging and age-related neurodegenerative pathologies such as Alzheimer’s disease (AD). Strategies for treating such impaired mitophagy would benefit from the identification of mitophagy modulators. Here we report the combined use of unsupervised machine learning (involving vector representations of molecular structures, pharmacophore fingerprinting and conformer fingerprinting) and a cross-species approach for the screening and experimental validation of new mitophagy-inducing compounds. From a library of naturally occurring compounds, the workflow allowed us to identify 18 small molecules, and among them two potent mitophagy inducers (Kaempferol and Rhapontigenin). In nematode and rodent models of AD, we show that both mitophagy inducers increased the survival and functionality of glutamatergic and cholinergic neurons, abrogated amyloid-β and tau pathologies, and improved the animals’ memory. Our findings suggest the existence of a conserved mechanism of memory loss across the AD models, this mechanism being mediated by defective mitophagy. The computational–experimental screening and validation workflow might help uncover potent mitophagy modulators that stimulate neuronal health and brain homeostasis.

The Post-COVID-19 cognitive impairment. A modern view of the problem, pathogenesis and treatment

COVID-19 infection is a significant and poorly understood problem of modern world medicine. As the virus spreads, data on the clinical picture of the disease and damage to the nervous system are accumulating. Symptoms such as fatigue, anxiety, depression, sleep disturbances and many other neurological and somatic symptoms are often recorded, persist for a long time even after the acute infectious stage of the disease has been stopped, and make it difficult for the patient to fully recover. These symptoms occur even with a mild disease and persist for many months. One of the most common and disabling symptoms of post-COVID syndrome is cognitive impairment, in the formation of which, in addition to the direct ability of the virus to penetrate the nervous system and pathology of the microvasculature, various pathological mechanisms are involved, including dysregulation of cholinergic transmission. A comprehensive approach is important in the treatment of cognitive impairment; it is advisable to use both medication and non-medication methods. The main approaches to the treatment of secondary cognitive disorders are based on the hypothesis of replenishing the defect in mediator systems, including those associated with the death of cholinergic neurons. With these abnormalities, it is advisable to replenish acetylcholine. Among the precursors of choline, choline alfoscerate occupies a special place due to its proven efficacy in the treatment of neurodegenerative diseases, as well as due to data on its multifactorial action. The article presents the actual literature data on the mechanisms of development and features of the clinical manifestations of post-COVID cognitive impairment, as well as materials of experimental and clinical studies of the drug choline alfoscerate (Gliatilin).

Uncovering a neural circuit controlling adult quiescent neural stem cell activation in the subventricular zone

The maintenance and differentiation of the adult neural stem cells (NSCs) in the subventricular zone (SVZ) are controlled by cell-intrinsic molecular pathways that interact with extrinsic signaling cues. How neurogenesis in the SVZ is regulated by neural circuit activity remains poorly understood. Here we identified a novel neural circuit that regulates the state of lateral ventricular wall (LV) NSCs. Our results demonstrate that direct glutamatergic inputs from the frontal cortex, as well as local inhibitory interneurons, control the activity of subependymal cholinergic neurons. In vivo optogenetic and chemogenetic stimulation of defined neuronal populations within this circuit were sufficient to control LV NSC proliferation and SVZ neurogenesis. Moreover, acetylcholine (ACh), which activates M1 muscarinic ACh receptors, triggers the activation of quiescent NSCs. These findings shed light on neural activity-dependent regulation of postnatal and adult LV NSCs activation and SVZ neurogenesis.

Oxidative Damage of Proteins Precedes Loss of Cholinergic Phenotype in the Septal Neurons of Olfactory Bulbectomized Mice

Background: The development of cholinergic deficit is considered an early sign of a number of pathological conditions, including Alzheimer’s disease. Cholinergic dysfunction underlies cognitive decline associated with both normal aging and Alzheimer’s disease. Objective: Here, we studied a possible mechanism of functional impairment of cholinergic neurons using an olfactory bulbectomy model. Methods: Male mice were subjected to olfactory bulbectomy or sham surgery. Three weeks after that they were trained in Morris water maze and then euthanized one month after surgery. The cholinergic indices as well as the indices of oxidative stress were studied using immunohistochemistry, western blot and ELISA. Gene expression was studied using RT-qPCR. Results: The experimental treatment was followed by impaired learning of a standard spatial task in a water maze. This was associated with a decrease in the number of cells containing choline acetyltransferase (ChAT), in relation to total number of neurons in the medial septum and lower ChAT enzymatic activity in the hippocampus. However, the levels of mRNAs of ChAT, vesicular ACh transporter and acetylcholine esterase remained unchanged in bulbectomized mice compared to sham-operated animals. These alterations were preceded by the accumulation of protein-bound carbonyls, indicating oxidative damage of proteins, whereas oxidative damage of nucleic acids was not detected. Conclusion: We assume that in olfactory bulbectomy model, oxidative damage of proteins may cause cholinergic dysfunction rather than irreversible neuronal damage. These data indicate that cholinergic neurons of the basal forebrain are very sensitive to oxidative stress, which may be responsible for the appearance of early cognitive decline in Alzheimer’s disease.

Enhanced Contractive Tension and Upregulated Muscarinic Receptor 2/3 in Colorectum Contribute to Constipation in 6-Hydroxydopamine-Induced Parkinson’s Disease Rats

Constipation and defecatory dysfunctions are frequent symptoms in patients with Parkinson’s disease (PD). The pathology of Lewy bodies in colonic and rectal cholinergic neurons suggests that cholinergic pathways are involved in colorectal dysmotility in PD. However, the underlying mechanism is unclear. The aim of the present study is to examine the effect of central dopaminergic denervation in rats, induced by injection 6-hydroxydopamine into the bilateral substania nigra (6-OHDA rats), on colorectal contractive activity, content of acetylcholine (ACh), vasoactive intestinal peptide (VIP) and expression of neural nitric oxide synthase (nNOS) and muscarinic receptor (MR). Strain gauge force transducers combined with electrical field stimulation (EFS), gut transit time, immunohistochemistry, ELISA, western blot and ultraperformance liquid chromatography tandem mass spectrometry were used in this study. The 6-OHDA rats exhibited outlet obstruction constipation characterized by prolonged transit time, enhanced contractive tension and fecal retention in colorectum. Pretreatment with tetrodotoxin significantly increased the colorectal motility. EFS-induced cholinergic contractions were diminished in the colorectum. Bethanechol chloride promoted colorectal motility in a dose-dependent manner, and much stronger reactivity of bethanechol chloride was observed in 6-OHDA rats. The ACh, VIP and protein expression of nNOS was decreased, but M2R and M3R were notably upregulated in colorectal muscularis externa. Moreover, the number of cholinergic neurons was reduced in sacral parasympathetic nucleus (SPN) of 6-OHDA rats. In conclusion, central nigrostriatal dopaminergic denervation is associated with decreased cholinergic neurons in SPN, decreased ACh, VIP content, and nNOS expression and upregulated M2R and M3R in colorectum, resulting in colorectal dysmotility, which contributes to outlet obstruction constipation. The study provides new insights into the mechanism of constipation and potential therapeutic targets for constipation in PD patients.

The Nerve Growth Factor Metabolic Pathway Dysregulation as Cause of Alzheimer’s Cholinergic Atrophy

The cause of the loss of basal forebrain cholinergic neurons (BFCNs) and their terminal synapses in the cerebral cortex and hippocampus in Alzheimer’s disease (AD) has provoked a decades-long controversy. The cholinergic phenotype of this neuronal system, involved in numerous cognitive mechanisms, is tightly dependent on the target-derived nerve growth factor (NGF). Consequently, the loss of BFCNs cholinergic phenotype in AD was initially suspected to be due to an NGF trophic failure. However, in AD there is a normal NGF synthesis and abundance of the NGF precursor (proNGF), therefore the NGF trophic failure hypothesis for the atrophy of BCNs was abandoned. In this review, we discuss the history of NGF-dependency of BFCNs and the atrophy of these neurons in Alzheimer’s disease (AD). Further to it, we propose that trophic factor failure explains the BFCNs atrophy in AD. We discuss evidence of the occurrence of a brain NGF metabolic pathway, the dysregulation of which, in AD explains the severe deficiency of NGF trophic support for the maintenance of BFCNs cholinergic phenotype. Finally, we revise recent evidence that the NGF metabolic dysregulation in AD pathology starts at preclinical stages. We also propose that the alteration of NGF metabolism-related markers in body fluids might assist in the AD preclinical diagnosis.

Choline Transporter regulates olfactory habituation via a neuronal triad of excitatory, inhibitory and mushroom body neurons

Choline is an essential component of Acetylcholine (ACh) biosynthesis pathway which requires high-affinity Choline transporter (ChT) for its uptake into the presynaptic terminals of cholinergic neurons. Previously, we had reported a predominant expression of ChT in memory processing and storing region of the Drosophila brain called mushroom bodies (MBs). It is unknown how ChT contributes to the functional principles of MB operation. Here, we demonstrate the role of ChT in Habituation, a non-associative form of learning. Odour driven habituation traces are laid down in ChT dependent manner in antennal lobes (AL), projection neurons (PNs), and MBs. We observed that reduced habituation due to knock-down of ChT in MBs causes hypersensitivity towards odour, suggesting that ChT also regulates incoming stimulus suppression. Importantly, we show for the first time that ChT is not unique to cholinergic neurons but is also required in inhibitory GABAergic neurons to drive habituation behaviour. Our results support a model in which ChT regulates both habituation and incoming stimuli through multiple circuit loci via an interplay between excitatory and inhibitory neurons. Strikingly, the lack of ChT in MBs shows characteristics similar to the major reported features of Autism spectrum disorders (ASD), including attenuated habituation, sensory hypersensitivity as well as defective GABAergic signalling. Our data establish the role of ChT in habituation and suggest that its dysfunction may contribute to neuropsychiatric disorders like ASD.