Protective Effects against the Development of Alzheimer's Disease in an Animal Model through Active Immunization with Methionine-Sulfoxide Rich Protein Antigen.

The brain during Alzheimer's disease (AD) is under severe oxidative attack by reactive oxygen species that may lead to methionine oxidation. Oxidation of the sole methionine (Met35) of beta-amyloid (Aß), and possibly methionine residues of other extracellular proteins, may be one of the earliest events contributing to the toxicity of Aß and other proteins in vivo. In the current study, we immunized transgenic AD (APP/PS1) mice at 4 months of age with a recombinant methionine sulfoxide (MetO)-rich protein from Zea mays (antigen). This treatment induced the production of anti-MetO antibody in blood-plasma that exhibits a significant titer up to at least 10 months of age. Compared to the control mice, the antigen-injected mice exhibited the following significant phenotypes at 10 months of age: better short and long memory capabilities; reduced Aß levels in both blood-plasma and brain; reduced Aß burden and MetO accumulations in astrocytes in hippocampal and cortical regions; reduced levels of activated microglia; and elevated antioxidant capabilities (through enhanced nuclear localization of the transcription factor Nrf2) in the same brain regions. These data collected in a preclinical AD model are likely translational, showing that active immunization could give a possibility of delaying or preventing AD onset. This study represents a first step toward the complex way of starting clinical trials in humans and conducting the further confirmations that are needed to go in this direction.

Pair Bond-Induced Affiliation and Aggression in Male Prairie Voles Elicit Distinct Functional Connectivity in the Social Decision-Making Network.

Complex social behaviors are governed by a neural network theorized to be the social decision-making network (SDMN). However, this theoretical network is not tested on functional grounds. Here, we assess the organization of regions in the SDMN using c-Fos, to generate functional connectivity models during specific social interactions in a socially monogamous rodent, the prairie voles (Microtus ochrogaster). Male voles displayed robust selective affiliation toward a female partner, while exhibiting increased threatening, vigilant, and physically aggressive behaviors toward novel males and females. These social interactions increased c-Fos levels in eight of the thirteen brain regions of the SDMN. Each social encounter generated a distinct correlation pattern between individual brain regions. Thus, hierarchical clustering was used to characterize interrelated regions with similar c-Fos activity resulting in discrete network modules. Functional connectivity maps were constructed to emulate the network dynamics resulting from each social encounter. Our partner functional connectivity network presents similarities to the theoretical SDMN model, along with connections in the network that have been implicated in partner-directed affiliation. However, both stranger female and male networks exhibited distinct architecture from one another and the SDMN. Further, the stranger-evoked networks demonstrated connections associated with threat, physical aggression, and other aversive behaviors. Together, this indicates that distinct patterns of functional connectivity in the SDMN can be detected during select social encounters.

Distinct Functional Connectivity Patterns Are Associated With Social and Cognitive Lifestyle Factors: Pathways to Cognitive Reserve.

The importance of diverse lifestyle factors in sustaining cognition during aging and delaying the onset of decline in Alzheimer's disease and related dementias cannot be overstated. We explored the influence of cognitive, social, and physical lifestyle factors on resting-state lagged linear connectivity (LLC) in high-density electroencephalography (EEG) in adults, ages 35-75 years. Diverse lifestyle factors build cognitive reserve (CR), protecting cognition in the presence of physical brain decline. Differences in LLC were examined between high- and low-CR groups formed using cognitive, social, and exercise lifestyle factors. LLC is a measure of lagged coherence that excludes zero phase contributions and limits the effects of volume conduction on connectivity estimates. Significant differences in LLC were identified for cognitive and social factors, but not exercise. Participants high in social CR possessed greater local and long-range connectivity in theta and low alpha for eyes-open and eyes-closed recording conditions. In contrast, participants high in cognitive CR exhibited greater eyes-closed long-range connectivity between the occipital lobe and other cortical regions in low alpha. Greater eyes-closed local LLC in delta was also present in men high in cognitive CR. Cognitive factor scores correlated with sustained attention, whereas social factors scores correlated with spatial working memory. Gender was a significant covariate in our analyses, with women displaying higher local and long-range LLC in low beta. Our findings support distinct relationships between CR and LLC, as well as CR and cognitive function for cognitive and social subcomponents. These patterns reflect the importance of diverse lifestyle factors in building CR.