Cristina Municio

Lactoferrin is present in brain cells and is known to protect against injury through anti-inflammatory and immunomodulatory processes. Furthermore, it has also been found within amyloid plaques in Alzheimer’s disease (AD), leading to the hypothesis that its presence in the AD brain may be detrimental. However, the identity of the brain cells that produce lactoferrin and how its expression changes in AD remain unclear. In this study, we examined lactoferrin expression and localization in 3- and 12-month-old male and female APP/PS1 mice. Using a microglial enrichment protocol and confocal imaging, we identified microglia as an important source of brain lactoferrin, and demonstrated that its expression is modulated by age, sex, and amyloid burden. In female mice, microglial lactoferrin expression was increased at both the mRNA and protein levels in 3-month-old APP/PS1 mice compared with age-matched wild-type controls. Conversely, lactoferrin transcript in the enrichment fraction, and protein localization were also reduced in microglia from 12-month-old female APP/PS1 mice, coinciding with increased amyloid burden. We further demonstrated that gene expression of lactoferrin follows daily variations under a light–dark cycle, similar to established microglial markers such as Iba1 and P2ry12, with alterations in this rhythmic pattern in APP/PS1 mice occurring predominantly in females. In addition, our findings suggest that neurons may internalize lactoferrin via LRP1, whose expression is downregulated by amyloid burden. This Aβ-dependent relationship was further corroborated in both microglial and neuronal in vitro models. Collectively, these findings identify microglia as an important source of lactoferrin in the brain. We suggest that sex- and age-dependent alterations in microglial lactoferrin expression may contribute to the sexual dimorphism observed in AD, possibly through alterations in LRP1-mediated neuronal uptake.

The choroid plexus (ChP) is a specialised tissue of the central nervous system that produces cerebrospinal fluid (CSF), maintains cerebral homeostasis and forms the blood-CSF barrier (B-CSF-B), a key interface that regulates the exchange of substances between the blood and the brain. Despite its physiological importance, the involvement of the ChP in neurodegenerative diseases such as Alzheimer’s disease (AD), remains poorly understood. This is largely due to the reliance on murine models and the limited availability of human brain tissue. Recent advances in human stem-cell derived ChP organoids now offer a more physiologically relevant model to interrogate ChP role in human health and disease. Given that in AD pathology beta-amyloid (Aβ) accumulation has been linked to early disruption of brain barriers, studying the B-CSF-B is particularly relevant. Transthyretin (TTR), the predominant protein secreted by the ChP, is thought to play a role in the transport and clearance of Aβ, although its exact mechanisms are not yet fully elucidated. Here, we propose the use of ChP organoids to investigate the role of the B-CSF-B in amyloid uptake which may contribute to barrier dysfunction and disease progression in AD.

Dysfunction in circadian rhythms is a common occurrence in patients with Alzheimer's disease. A predominant function of the retina is circadian synchronization, carrying information to the brain through the retinohypothalamic tract, which projects to the suprachiasmatic nucleus. Notably, Alzheimer's disease hallmarks, including amyloid-β, are present in the retinas of Alzheimer's disease patients, followed/associated by structural and functional disturbances. However, the mechanistic link between circadian dysfunction and the pathological changes affecting the retina in Alzheimer's disease is not fully understood, although some studies point to the possibility that retinal dysfunction could be considered an early pathological process that directly modulates the circadian rhythm.

Alzheimer’s disease (AD), the most prevalent form of dementia, is a neurodegenerative disorder characterized by different pathological symptomatology, including disrupted circadian rhythm. The regulation of circadian rhythm depends on the light information that is projected from the retina to the suprachiasmatic nucleus in the hypothalamus. Studies of AD patients and AD transgenic mice have revealed AD retinal pathology, including amyloid-β (Aβ) accumulation that can directly interfere with the regulation of the circadian cycle. Although the cause of AD pathology is poorly understood, one of the main risk factors for AD is female gender. Here, we found that female APP/PS1 mice at 6- and 12-months old display severe circadian rhythm disturbances and retinal pathological hallmarks, including Aβ deposits in retinal layers. Since brain Aβ transport is facilitated by aquaporin (AQP)4, the expression of AQPs were also explored in APP/PS1 retina to investigate a potential correlation between retinal Aβ deposits and AQPs expression. Important reductions in AQP1, AQP4, and AQP5 were detected in the retinal tissue of these transgenic mice, mainly at 6-months of age. Taken together, our findings suggest that abnormal transport of Aβ, mediated by impaired AQPs expression, contributes to the retinal degeneration in the early stages of AD.

The circadian clock is synchronized to the 24 h day by environmental light which is transmitted from the retina to the suprachiasmatic nucleus (SCN) primarily via the retinohypothalamic tract (RHT). Circadian rhythm abnormalities have been reported in neurodegenerative disorders such as Alzheimer's disease (AD). Whether these AD-related changes are a result of the altered clock gene expression, retina degeneration, including the dysfunction in RHT transmission, loss of retinal ganglion cells and its electrophysiological capabilities, or a combination of all of these pathological mechanisms, is not known. Here, we evaluated transgenic APP/PS1 mouse model of AD and wild-type mice at 6- and 12-month-old, as early and late pathological stage, respectively. We noticed the alteration of circadian clock gene expression not only in the hypothalamus but also in two extra-hypothalamic brain regions, cerebral cortex and hippocampus, in APP/PS1 mice. These alterations were observed in 6-month-old transgenic mice and were exacerbated at 12 months of age. This could be explained by the reduced RHT projections in the SCN of APP/PS1 mice, correlating with downregulation of hypothalamic GABAergic response in APP/PS1 mice in advanced stage of pathology. Importantly, we also report retinal degeneration in APP/PS1 mice, including Aβ deposits and reduced choline acetyltransferase levels, loss of melanopsin retinal ganglion cells and functional integrity mainly of inner retina layers. Our findings support the theory that retinal degeneration constitutes an early pathological event that directly affects the control of circadian rhythm in AD.

The glymphatic system, a fluid-clearance pathway involved in brain waste clearance, is known to be impaired in neurological disorders, including Alzheimer’s disease (AD). For this reason, it is important to understand the specific mechanisms and factors controlling glymphatic function. This pathway enables the flow of cerebrospinal fluid (CSF) into the brain and subsequently the brain interstitium, supported by aquaporins (AQPs). Continuous CSF transport through the brain parenchyma is critical for the effective transport and drainage of waste solutes, such as toxic proteins, through the glymphatic system. However, a balance between CSF production and secretion from the choroid plexus, through AQP regulation, is also needed. Thus, any condition that affects CSF homeostasis will also interfere with effective waste removal through the clearance glymphatic pathway and the subsequent processes of neurodegeneration. In this review, we highlight the role of AQPs in the choroid plexus in the modulation of CSF homeostasis and, consequently, the glymphatic clearance pathway, with a special focus on AD.