Alzheimer’s disease (AD) is characterized by the loss of neurons. It is the most common cause of dementia in the elderly population accompanied by pathological degeneration of neurofibrillary tangles. Senile plaques are formed with beta-amyloid, hyperphosphoryled tau protein, apolipoprotein E and presenilin associated with protease activity [amyloid beta (Aβ), gamma-secretase (γS)]. The molecular mechanisms of neurodegeneration include apoptosis, oxidative stress (free radical generation), inflammation, immune activation, and others. The lack of effective treatments for AD stems mainly from the incomplete understanding the causes of AD. Currently, there are several hypotheses explaining the early mechanisms of AD pathogenesis. Recent years witnessed an unprecedented research growth in the area of nanotechnology, which uses atomic, molecular and macromolecular methods to create products in microscale (nanoscale) dimensions. In this article, we have discussed the role of nanotechnology in the development and improvement of techniques for early diagnosis and effective treatment of AD. Since AD pathology is practically irreversible, applications of disease-modifying treatments could be successful only if early diagnosis of AD is available. This review highlights various possibilities for the early diagnosis and therapy of AD and investigates potential adaptation of nanoparticles-dendrimers as a class of well-defined branched polymers that are chemically synthesized with a well-defined shape, size and nanoscopic physicochemical properties reminiscent of the proteins for the treatment of neurodegenerative diseases.

Cognitive malfunction, synaptic dysfunction, and disconnections in neural networks are core deficits in Alzheimer's disease (AD). 5xFAD mice, a transgenic model of AD, are characterised by an enhanced level of amyloid-beta and abnormal neurotransmission. The dopaminergic (DA) system has been shown to be involved in amyloid-beta transformations and neuronal plasticity; however, its role in functional network changes in familial AD still remains unclear. In 5xFAD and non-transgenic freely moving mice, electroencephalograms (EEGs) were simultaneously recorded from the secondary motor cortex (MC), superficial layers of the hippocampal CA1 area (HPC), substantia nigra (SN), and ventral tegmental area (VTA). EEGs and their frequency spectra were analysed before and after systemic injection of a DA receptor agonist, apomorphine (APO). In the baseline EEG from MC and HPC of 5xFAD mice, delta and alpha oscillations were enhanced and beta activity was attenuated, compared to control mice. In VTA and SN of 5xFAD mice, delta-theta activity was decreased and beta oscillations dominated. In control mice, APO suppressed delta activity in VTA to a higher extent than in MC, whereas in 5xFAD mice, this difference was eliminated due to attenuation of the delta suppression in VTA. APO increased beta activity in MC of mice from both groups while significant beta suppression was observed in VTA of 5xFAD mice. These mice were characterized by significant decrease of tyrosine hydroxylase immunopositive cells in both VTA and SN and of DA transporter in MC and hippocampal dentate gyrus. We suggest that the EEG modifications observed in 5xFAD mice are associated with alterations in dopaminergic transmission, resulting in adaptive changes in the cerebral networks in the course of familial AD development.

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Mutations in a gene encoding RNA-binding protein FUS was linked to familial forms of amyotrophic lateral sclerosis (ALS). C-terminal truncations of FUS are associated with aggressive forms of ALS. However, motor neurons are able to tolerate permanent production of pathogenic truncated form of FUS protein until its accumulation in the cytoplasm of neurones does not reach a critical threshold.In order to identify how the nervous system responds to pathogenic variants of FUS we produced and characterised a mouse line, L-FUS[1-359], with a low level of neuronal expression of a highly aggregation prone and pathogenic form of C-terminally truncated FUS. In contrast to mice with substantially higher level of expression of the same FUS variant that develop severe early onset motor neuron pathology, L-FUS[1-359] mice do not develop any sign of pathology even at old age.Nevertheless, we detected substantial changes in the spinal cord transcriptome of these mice comparing to the wild type littermates. We suggest that at least some of these changes reflect activation of cellular mechanisms compensating to potentially damaging effect of pathogenic FUS production. Further studies of these mechanism might reveal effective target for therapy of FUS-ALS and possibly, other forms of ALS.

The discovery of drugs for diseases of the central nervous system (CNS) faces high attrition rates in clinical trials. Neural diseases are extremely complex in nature and typically associated with multiple drug targets. A conception of multi-target directed ligands (MTDL), widely applied to the discovery of cancer pharmaceuticals, may be a perspective solution for CNS diseases. Special bioinformatics approaches have been developed which can assist the medicinal chemists in identification and structural optimization of MTDL. In this review, we analyze the current status of the development of multitarget approaches in quantitative structure-activity relationships (mt-QSAR) for CNS drug discovery; and describes applications of multi-target approaches in molecular modelling (which can be called mt-MM), as well as perspectives for multi-target approaches in bioinformatics in relation to Alzheimer’s disease.