Unique Properties of Synaptosomes and Prospects for Their Use for the Treatment of Alzheimer's Disease.

Alzheimer's disease (AD) is a severe neurodegenerative condition affecting millions worldwide. Prevalence of AD correlates with increased life expectancy and aging population in the developed countries. Considering that AD is a multifactorial disease involving various pathological processes such as synaptic dysfunction, neuroinflammation, oxidative stress, and improper protein folding, a comprehensive approach targeting multiple pathways may prove effective in slowing the disease progression.

Intranasal administration of mitochondria improves spatial memory in olfactory bulbectomized mice.

Here, we found that functionally active mitochondria isolated from the brain of NMRI donor mice and administrated intranasally to recipient mice penetrated the brain structures in a dose-dependent manner. The injected mitochondria labeled with the MitoTracker Red localized in different brain regions, including the neocortex and hippocampus, which are responsible for memory and affected by degeneration in patients with Alzheimer's disease. In behavioral experiments, intranasal microinjections of brain mitochondria of native NMRI mice improved spatial memory in the olfactory bulbectomized (OBX) mice with Alzheimer's type degeneration.

Proteolytic degradation patterns of the receptor for advanced glycation end products peptide fragments correlate with their neuroprotective activity in Alzheimer's disease models.

The receptor for advanced glycation end products (RAGE) plays an essential role in Alzheimer's disease (AD). We previously demonstrated that a fragment (60-76) of RAGE improved the memory of olfactory bulbectomized (OBX) and Tg 5 × FAD mice - animal models of AD. The peptide analog (60-76) with protected N- and C-terminal groups was more active than the free peptide in Tg 5 × FAD mice.

Synthetic Fragments of Receptor for Advanced Glycation End Products Bind Beta-Amyloid 1-40 and Protect Primary Brain Cells From Beta-Amyloid Toxicity.

Receptor for advanced glycation end products (RAGE) is involved in the pathogenesis of Alzheimer's disease. We have previously revealed that RAGE fragment sequence (60-76) and its shortened analogs sequence (60-70) and (60-65) under intranasal insertion were able to restore memory and improve morphological and biochemical state of neurons in the brain of bulbectomized mice developing major AD features. In the current study, we have investigated the ability of RAGE peptide (60-76) and five shortened analogs to bind beta-amyloid (Aβ) 1-40 in an fluorescent titration test and show that all the RAGE fragments apart from one [sequence (65-76)] were able to bind Aβ .

Effect of weak combined static and extremely low-frequency alternating magnetic fields on spatial memory and brain amyloid-β in two animal models of Alzheimer's disease.

Subchronic effect of a weak combined magnetic field (MF), produced by superimposing a constant component, 42 µT and an alternating MF of 0.08 µT, which was the sum of two frequencies of 4.38 and 4.

Synthetic Fragment of Receptor for Advanced Glycation End Products Prevents Memory Loss and Protects Brain Neurons in Olfactory Bulbectomized Mice.

Activation of receptor for advanced glycation end products (RAGE) plays an essential role in the development of Alzheimer's disease (AD). It is known that the soluble isoform of the receptor binds to ligands and prevents negative effects of the receptor activation. We proposed that peptide fragments from RAGE prevent negative effects of the receptor activation during AD neurodegeneration.

Molecular Mechanisms Underlying Neuroprotective Effect of Intranasal Administration of Human Hsp70 in Mouse Model of Alzheimer's Disease.

Heat shock protein 70, encoded by the HSPA1A gene in humans, is a key component of the machinery that protects neuronal cells from various stress conditions and whose production significantly declines during the course of aging and as a result of several neurodegenerative diseases. Herein, we investigated whether sub-chronic intranasal administration of exogenous Hsp70 (eHsp70) exerts a neuroprotective effect on the temporal cortex and areas of the hippocampus in transgenic 5XFAD mice, a model of Alzheimer's disease. The quantitative analysis of neuronal pathologies in the compared groups, transgenic (Tg) versus non-transgenic (nTg), revealed high level of abnormalities in the brains of transgenic mice.

Interplay between recombinant Hsp70 and proteasomes: proteasome activity modulation and ubiquitin-independent cleavage of Hsp70.

The heat shock protein 70 (Hsp70, human HSPA1A) plays indispensable roles in cellular stress responses and protein quality control (PQC). In the framework of PQC, it cooperates with the ubiquitin-proteasome system (UPS) to clear damaged and dysfunctional proteins in the cell. Moreover, Hsp70 itself is rapidly degraded following the recovery from stress.

Exogenous Hsp70 delays senescence and improves cognitive function in aging mice.

Molecular chaperone Heat Shock Protein 70 (Hsp70) plays an important protective role in various neurodegenerative disorders often associated with aging, but its activity and availability in neuronal tissue decrease with age. Here we explored the effects of intranasal administration of exogenous recombinant human Hsp70 (eHsp70) on lifespan and neurological parameters in middle-aged and old mice. Long-term administration of eHsp70 significantly enhanced the lifespan of animals of different age groups.

The Fate of Exogenous Human HSP70 Introduced into Animal Cells by Different Means.

Over the last decade, it has become evident that in mammals, including humans, heat shock protein 70 (HSP70), apart from its intracellular localization, is found in extracellular space, where it may execute various protective functions. Furthermore, the upregulation of HSP70 family members can be beneficial in the prevention and treatment of various human neurodegenerative diseases and cancer. Here, we demonstrate that recombinant human HSP70 after intranasal administration can penetrate various brain regions of mice in its native form and subsequently undergo rapid degradation.

Therapeutic effect of exogenous hsp70 in mouse models of Alzheimer's disease.

Brain deterioration resulting from "protein folding" diseases, such as the Alzheimer's disease (AD), is one of the leading causes of morbidity and mortality in the aging human population. Heat shock proteins (Hsps) constitute the major cellular quality control system for proteins that mitigates the pathological burden of neurotoxic protein fibrils and aggregates. However, the therapeutic effect of Hsps has not been tested in a relevant setting.