Oxidized cholesterol metabolite 27‐hydroxycholesterol (27‐OH) is a potential link between hypercholesterolemia and neurodegenerative diseases since unlike peripheral cholesterol, 27‐OH is transported across the blood–brain barrier. However, the effects of high 27‐OH levels on oligodendrocyte function remain unexplored. We hypothesize that during hypercholesterolemia 27‐OH may impact oligodendrocytes and myelin and thus contribute to the disconnection of neural networks in neurodegenerative diseases. To test this idea, we first investigated the effects of 27‐OH in cultured oligodendrocytes and found that it induces cell death of immature O4+/GalC+ oligodendrocytes along with stimulating differentiation of PDGFR+ oligodendrocyte progenitors (OPCs). Next, transgenic mice with increased systemic 27‐OH levels (Cyp27Tg) underwent behavioral testing and their brains were immunohistochemically stained and lysed for immunoblotting. Chronic exposure to 27‐OH in mice resulted in increased myelin basic protein (MBP) but not 2′,3′‐cyclic‐nucleotide 3′‐phosphodiesterase (CNPase) or myelin oligodendrocyte glycoprotein (MOG) levels in the corpus callosum and cerebral cortex. Intriguingly, we also found impairment of spatial learning suggesting that subtle changes in myelinated axons of vulnerable areas like the hippocampus caused by 27‐OH may contribute to impaired cognition. Finally, we found that 27‐OH levels in cerebrospinal fluid from memory clinic patients were associated with levels of the myelination regulating CNPase, independently of Alzheimer's disease markers. Thus, 27‐OH promotes OPC differentiation and is toxic to immature oligodendrocytes as well as it subtly alters myelin by targeting oligodendroglia. Taken together, these data indicate that hypercholesterolemia‐derived higher 27‐OH levels change the oligodendrocytic capacity for appropriate myelin remodeling which is a crucial factor in neurodegeneration and aging.

Since developing an effective treatment for Alzheimer’s disease (AD) has been encountered as a challenging task, attempts to prevent cognitive decline by lifestyle modifications have become increasingly appealing. Physical exercise, healthy diet, and cognitive training are all modifiable, non-pharmacological lifestyle factors considered to influence cognitive health. Implementing lifestyle modifications on animal models of AD and cognitive impairment may reveal underlying mechanisms of action by which healthy lifestyle contribute to brain health. In mice, different types of lifestyle interventions have been shown to improve cognitive abilities, alleviate AD-related pathology and neuroinflammation, restore mitochondrial function, and have a positive impact on neurogenesis and cell survival. Different proteins and pathways have been identified to mediate some of the responses, amongst them BDNF, Akt–GSK3β, JNK, and ROCK pathway. Although some important pathways have been identified as mediating improvements in brain health, more research is needed to confirm these mechanisms of action and to improve the understanding of their interplay. Moreover, multidomain lifestyle interventions targeting multiple risk factors simultaneously may be a promising avenue in future dementia prevention strategies. Therefore, future work is needed to better understand the synergistic impact of combinatory lifestyle strategies on cellular mechanisms and brain health.

Alzheimer's disease is a multifactorial disorder with a heterogeneous patient population. Comorbidities such as hypertension, hypercholesterolemia and diabetes are known contributors to the disease progression. Indeed, therapies targeting these disorders have been shown efficient in dementia prevention. However, their mechanistic contribution to Alzheimer's pathology and neurodegeneration has not been fully clarified. In the current study, we used CSF samples from a memory clinic cohort of 90 patients without diagnosed hypertension, hypercholesterolemia, or diabetes nor other neurodegenerative disorder, to investigate 13 molecular markers representing key mechanisms underlying Alzheimer's pathogenesis. Levels were compared between clinical groups of subjective cognitive decline, mild cognitive impairment, and Alzheimer's disease. Associations between markers and groups of markers were analyzed by linear regression. Two-step cluster analysis was used to determine patient clusters. Two key markers were further analyzed by immunofluorescence staining in hippocampus from control and AD individuals without hypertension, hypercholesterolemia nor diabetes. CSF angiotensinogen, thioredoxin-1, and interleukin-15 were the biomarkers with the most prominent associations with Alzheimer's pathology, synaptic and axonal damage. Synaptosomal-associated protein 25 kDa and neurofilament light chain were increased in mild cognitive impairment and Alzheimer cases. When we grouped biomarkers by biological function, we found that inflammatory and survival components were associated with Alzheimer's pathology, synaptic dysfunction and axonal damage. Moreover, a vascular/metabolic component was associated with synaptic dysfunction. In data-driven analysis, two patient clusters were identified; Older participants with increased CSF markers of oxidative stress, vascular pathology and neuroinflammation were assigned to cluster 1, that was also smaller and characterized by increased synaptic and axonal damage, compared to individuals in cluster 2. Clinical groups were evenly distributed between the clusters. Analysis of post-mortem hippocampal tissue, showed that, compared to controls, angiotensinogen staining was higher in Alzheimer's disease and was also found to co-localize with phosphorylated-tau. In a population free of common comorbidities, we could still find associations between Alzheimer's disease biomarkers and markers of pathways associated with increased risk for Alzheimer's disease (i.e., neuroinflammation, vascular function, oxidative stress and cholesterol homeostasis), suggesting that these pathways are contributing to Alzheimer's disease mechanisms even in absence of clinically diagnosed comorbidities. The identification of distinct biomarker-driven endophenotypes of cognitive disorder patients, further highlights the biological heterogeneity of Alzheimer's disease and the importance of developing tailored prevention and treatment strategies.

Background: Midlife hypercholesterolemia is a risk factor for dementia, possibly via vascular-related pathways. Another proposed factor linking elevated systemic cholesterol levels and neurodegenerative diseases is the oxidized cholesterol metabolite 27-hydroxycholesterol (27-OH) that is able to pass the blood-brain barrier. High levels of 27-OH harm neuronal integrity and function, yet the effect of high 27-OH levels on oligodendrocyte function remains unexplored. Since abnormal myelin structure results in the disconnection of neural networks that is an early phenomenon in neurodegenerative diseases, this study aimed to determine whether 27-OH affects myelination in the brain. Methods: Effects of 27-OH treatment were investigated both in isolated and co-cultured oligodendrocytes. Transgenic female mice with increased systemic 27-OH levels (Cyp27Tg) underwent behavioural testing and their brains were immunohistochemically stained and lysed for immunoblotting. CSF samples from a memory clinic cohort were analysed for associations between 27-OH and myelin proteins. Results: Whereas human oligodendroglioma cells were resistant to high levels of 27-OH (10 µM), cell death was induced in primary rat oligodendrocytes already at low concentrations (0.5 µM). Long-term effects from treatment with 1 µM 27-OH stimulated differentiation of oligodendrocytes in murine 3D co-cultures. Female Cyp27Tg mice demonstrated learning deficits in the Morris Water Maze compared to non-transgenic littermates. Levels of myelin basic protein were increased in the corpus callosum of Cyp27Tg mice but adenomatous polyposis coli clone 1 (CC1) and platelet-derived growth factor receptor α (PDGFR1α) were unaltered, while levels of myelin oligodendrocyte glycoprotein were decreased in myelin enriched fractions. Levels of 27-OH in the CSF of memory clinic patients were associated with increased levels of the oligodendrogenesis regulating enzyme 2',3'-Cyclic-nucleotide 3'-phosphodiesterase (CNPase; β = 0.38, p = 0.022). Conclusions: The hypercholesterolemia associated 27-OH alters the rate of differentiation from progenitor cells into mature oligodendrocytes and influences oligodendrocyte viability suggesting that 27-OH reduces the oligodendrocytic ability for appropriate remodelling in the ageing brain by reducing the pool of progenitor cells.

Background:The heterogeneity of a multifactorial disease like Alzheimer's disease (AD) cannot be captured solely with ATN biomarkers. Previous research has identified mixed neuropathologies as well as subtypes discovered by brain scans and cerebrospinal fluid (CSF) proteomics in AD cohorts. Still, we need a better understanding of how clinical characteristics distribute between subgroups of AD. Additionally, various approaches determining subgroups need to be evaluated. AD, which falls under the umbrella term dementia, could in fact also be considered an umbrella itself with distinct subgroups.Method: Altogether 288 CSF samples from patients from the Karolinska University Hospital memory clinic in Solna, Sweden, were analysed. Patients in the cohort were diagnosed with subjective cognitive impairment (SCI), mild cognitive impairment (MCI), and different dementias, mainly AD. Using an antibody-based suspension bead array, levels of 75 proteins were measured. Clustering analysis methods were used to identify subgroups. Result:The assessed panel reveals differences in patterns of protein levels within diagnostic groups and by applying clustering analyses subgroups across the dementia spectrum can be identified. Furthermore, Gene Ontology search implies differences in plausible underlying disease mechanisms between the distinct subgroups. It is of interest to explore to what extent, e.g., cardiovascular conditions or psychological burden are represented in the subgroups. Conclusion:Identifying subgroups within different diagnostic groups may prove to be crucial for finding the most suitable prevention and treatment options, particularly when disease modifying drugs are developed and tested.