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INTRODUCTION: Understanding impact of environmental properties on Alzheimer's disease (AD) is paramount. Spatial complexity of one's routinely navigated environment is an important but understudied factor. METHODS: A total of 660 older adults from National Alzheimer's Coordinating Center (NACC) dataset were geolocated and environmental complexity index derived from geospatial network landmarks and points-of-interest. Latent models tested mediation of spatial navigation-relevant brain volumes and diagnosis (cognitively-healthy, mild cognitive impairment [MCI], AD) on effect of environmental complexity on spatial behavior. RESULTS: Greater environmental complexity was selectively associated with larger allocentric (but not egocentric) navigation-related brain volumes, lesser diagnosis of MCI and AD, and better spatial behavioral performance, through indirect hierarchical mediation. DISCUSSION: Findings support hypothesis that spatially complex environments positively impact navigation neural circuitry and spatial behavior function. Given the vulnerability of these very circuits to AD pathology, residing in spatially complex environments may be one factor to help stave off the brain atrophy that accompanies spatial navigation deficits across the AD spectrum.

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Recent clinical approvals of brain imaging radiotracers targeting amyloid-ß provided clinicians the tools to detect and confirm Alzheimer's disease pathology without autopsy or biopsy. While current imaging agents are effective in postsymptomatic Alzheimer's patients, there is much room for improvement in earlier diagnosis, hence prompting a need for new and improved amyloid imaging agents. Here we synthesized 41 novel 1,4-naphthoquinone derivatives and initially discovered 14 antiamyloidogenic compounds via in vitro amyloid-ß aggregation assay; however, qualitative analyses of these compounds produced conflicting results and required further investigation. Follow-up docking and biophysical studies revealed that four of these compounds penetrate the blood-brain barrier, directly bind to amyloid-ß aggregates, and enhance fluorescence properties upon interaction. These compounds specifically stain both diffuse and dense-core amyloid-ß plaques in brain sections of APP/PS1 double transgenic Alzheimer's mouse models. Our findings suggest 1,4-naphthoquinones as a new scaffold for amyloid-ß imaging agents for early stage Alzheimer's.

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Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the formation of toxic amyloid-ß (Aß) oligomers and plaques. Considering that Aß misfolding and aggregation precedes the progressive development of cognitive impairment in AD, investigating a therapeutic means by clearance of pre-existing Aß aggregates shows promise as a viable disease-modifying treatment. Here, we report that a small molecule, necrostatin-1 (Nec-1), reduces Aß aggregates back to non-toxic monomers in vitro and in vivo. Intravenous administration of Nec-1 reduced the levels of Aß plaques in the brains of aged APP/PS1 double transgenic mice. In addition, Nec-1 exhibited therapeutic effects against Aß aggregates by inhibiting Aß-induced brain cell death in neuronal and microglial cell lines. Nec-1 also showed anti-apoptotic and anti-necroptotic effects in the cortex of aged APP/PS1 mice by reducing levels of phosphorylated-RIPK3 and Bax and increasing the levels of Bcl-2. According to our data in vitro and in silico, the methyl group of the amine in the 2-thioxo-4-imidazolidinone is the key moiety of Nec-1 that directs its activity against aggregated Aß. Given that the accumulation of Aß aggregates is an important hallmark of AD, our studies provide strong evidence that Nec-1 may serve a key role in the development of AD treatment.

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Understanding the physiological implications of caging conditions for mice is crucial in improving the replicability and reliability of animal research. Individual caging of mice is known to alter mouse psychology, such as triggering depression-like symptoms in mice, suggesting that caging conditions could have negative effects on mice. Therefore, we hypothesized that individual caging could affect the physical composition of outbred mice. To investigate this, dual X-ray absorptiometry (DXA) was used to compare the mass, bone mineral content (BMC), bone mineral density (BMD), lean tissue percentage and fat tissue percentage between group and individual caged mice. We also conducted open field test to compare mouse activities in different caging conditions. Our results showed significantly reduced BMD and lean tissue percentage and significantly increased fat tissue percentage in individually-caged male mice. Furthermore, there were no differences in body mass and activity between the grouped and individual mice, suggesting that these physical alterations were not induced by group-related activity. In this study, we conclude that individual caging could alter the body composition of mice without affecting external morphology.

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