Alzheimer's disease (AD) has several hallmark features including amyloid-β plaque deposits and neuronal loss. Here, we characterized amyloid-β plaque aggregation and parvalbumin-positive (PV) GABAergic neurons in 6 -9 month old 5xFAD mice harboring mutations associated with familial AD. We used immunofluorescent staining to compare three regions in the frontal cortexprelimbic (PrL), cingulate (Cg, including Cg1 and Cg2) and secondary motor (M2) corticesalong with primary somatosensory (S1) cortex. We quantified the density of amyloid-β plaques, which showed significant laminar and regional vulnerability. There were more plaques of larger sizes in deep layers compared to superficial layers. Total plaque burden was higher in frontal regions compared to S1. We also found layer-and region-specific differences across genotype in the density of PV interneurons. PV neuron density was lower in 5xFAD mice than wild-type, particularly in deep layers of frontal regions, with Cg (−50%) and M2 (−39%) exhibiting the largest reduction. Using in vivo two-photon imaging, we longitudinally visualized the loss of frontal cortical PV neurons across four weeks in the AD mouse model. Overall, these results provide information about amyloid-β deposits and PV neuron density in a widely used mouse model for AD, implicating deep layers of frontal cortical regions as being especially vulnerable.

Background The brain requires iron for a number of processes, including energy production. Inadequate or excessive amounts of iron can be detrimental and lead to a number of neurological disorders. As such, regulation of brain iron uptake is required for proper functioning. Understanding both the movement of iron into the brain and how this process is regulated is crucial to both address dysfunctions with brain iron uptake in disease and successfully use the transferrin receptor uptake system for drug delivery. Methods Using in vivo steady state infusions of apo- and holo-transferrin into the lateral ventricle, we demonstrate the regulatory effects of brain apo- and holo-transferrin ratios on the delivery of radioactive 55Fe bound to transferrin or H-ferritin in male and female mice. In discovering sex differences in the response to apo- and holo-transferrin infusions, ovariectomies were performed on female mice to interrogate the influence of circulating estrogen on regulation of iron uptake. Results Our model reveals that apo- and holo-transferrin significantly regulate iron uptake into the microvasculature and subsequent release into the brain parenchyma and their ability to regulate iron uptake is significantly influenced by both sex and type of iron delivery protein. Furthermore, we show that cells of the microvasculature act as reservoirs of iron and release the iron in response to cues from the interstitial fluid of the brain. Conclusions These findings extend our previous work to demonstrate that the regulation of brain iron uptake is influenced by both the mode in which iron is delivered and sex. These findings further emphasize the role of the microvasculature in regulating brain iron uptake and the importance of cues regarding iron status in the extracellular fluid.

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