Circadian rhythm disruption and retinal dysfunction: a bidirectional link in Alzheimer's disease?

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-ß, 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.

Altered Clock Gene Expression in Female APP/PS1 Mice and Aquaporin-Dependent Amyloid Accumulation in the Retina.

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-ß (Aß) 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 Aß deposits in retinal layers. Since brain Aß 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 Aß 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 Aß, mediated by impaired AQPs expression, contributes to the retinal degeneration in the early stages of AD.

Disturbed circadian rhythm and retinal degeneration in a mouse model of Alzheimer's disease.

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 Aß 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.

Choroid Plexus Aquaporins in CSF Homeostasis and the Glymphatic System: Their Relevance for Alzheimer's Disease.

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.

Differentially Aquaporin 5 Expression in Submandibular Glands and Cerebral Cortex in Alzheimer's Disease.

Impaired brain clearance mechanisms may result in the accumulation of aberrant proteins that define Alzheimer's disease (AD). The water channel protein astrocytic aquaporin 4 (AQP4) is essential for brain amyloid-ß clearance, but it is known to be abnormally expressed in AD brains. The expression of AQPs is differentially regulated during diverse brain injuries, but, whereas AQP4 expression and function have been studied in AD, less is known about AQP5. AQP5 functions include not only water transport but also cell migration mediated by cytoskeleton regulation. Moreover, AQP5 has been reported to be expressed in astrocytes, which are regulated after ischemic and traumatic injury. Additionally, AQP5 is particularly abundant in the salivary glands suggesting that it may be a crucial factor in gland dysfunction associated with AD. Herein, we aim to determine whether AQP5 expression in submandibular glands and the brain was altered in AD. First, we demonstrated impaired AQP5 expression in submandibular glands in APP/PS1 mice and AD patients. Subsequently, we observed that AQP5 expression was upregulated in APP/PS1 cerebral cortex and confirmed its expression both in astrocytes and neurons. Our findings propose AQP5 as a significant role player in AD pathology, in addition to AQP4, representing a potential target for the treatment of AD.

Salivary Lactoferrin Expression in a Mouse Model of Alzheimer's Disease.

In the last few years, microbial infection and innate immune theories have been proposed as an alternative approach explaining the etiopathogenesis and origin of Alzheimer's disease (AD). Lactoferrin, one of the main antimicrobial proteins in saliva, is an important modulator of immune response and inflammation, and represents an important defensive element by inducing a broad spectrum of antimicrobial effects against microbial infections. We demonstrated that lactoferrin levels in saliva are decreased in prodromal and dementia stages of AD compared with healthy subjects. That finding seems to be specific to cerebral amyloid-ß (Aß) load as such observation was not observed in healthy elderly controls or those subjects with frontotemporal dementia. In the present study, we analysed salivary lactoferrin levels in a mouse model of AD. We observed robust and early reduction of lactoferrin levels in saliva from 6- and 12-month-old APP/PS1 mice. Because saliva is secreted by salivary glands, we presume that deregulation in salivary glands resulting in reduced salivary lactoferrin levels may occur in AD. To test this hypothesis, we collected submandibular glands from APP/PS1 mice, as well as submandibular gland tissue from AD patients and we analysed the expression levels of key components of the salivary protein signalling pathway. A significant reduction in M3 receptor levels was found along with decreased acetylcholine (Ach) levels in submandibular glands from APP/PS1 mice. Similarly, a reduction in M3 receptor levels was observed in human submandibular glands from AD patients but in that case, the Ach levels were found increased. Our data suggest that the ACh-mediated M3 signalling pathway is impaired in salivary glands in AD, resulting in salivary gland dysfunction and reduced salivary lactoferrin secretion.

Gongylonema sp. infection in the scops owl (Otus scops).

Since 1997, it has been observed that fledging scops owls often develop necrotic plaques in their oral cavities, which in severe cases can even affect bone tissue. This condition has been defined as a necrotic oropharyngeal disease based on gross lesions. In 2011 alone, thirty-five cases were identified at the Brinzal Owl Rescue Centre (Madrid, Spain), of which four were chosen to perform a complete diagnostic study. Histopathology was carried out in three cases and cytology in one case. Using morphological traits cytology identified two larvae as third-stage larvae of a Spiruridae nematode. Histology detected parasite sections in the mucosal epithelium of the mouth of one owl. In addition, four samples of mucosal lesions were subjected to a PCR amplification of the nematode ribosomal RNA gene using a pair of universal primers, three of which were positive. Of available sequences, the sequence obtained showed the closest affinity to that of Gongylonema pulchrum (97.8-98.0%). Clinical treatment was based on supportive therapy, the daily removal of caseous material from the oral cavity and the administration of fenbendazol (50mg/kg PO for 5 days). Approximately 60% of the affected scops owls that arrived at the rescue centre in 2011 were cured and released back into the wild. Clinical, pathological and molecular findings are consistent with Gongylonema sp. infection. Since no evidence of the presence of adult parasites was found, we suggest that these scops owls should be considered as accidental hosts. This is the first description of severe Gongylonema infection in fledgling scops owls, a disease can lead to starvation and death if proper treatment is not provided.