Erythrocyte adenosine A2B receptor prevents cognitive and auditory dysfunction by promoting hypoxic and metabolic reprogramming.

Hypoxia drives aging and promotes age-related cognition and hearing functional decline. Despite the role of erythrocytes in oxygen (O2) transport, their role in the onset of aging and age-related cognitive decline and hearing loss (HL) remains undetermined. Recent studies revealed that signaling through the erythrocyte adenosine A2B receptor (ADORA2B) promotes O2 release to counteract hypoxia at high altitude. However, nothing is known about a role for erythrocyte ADORA2B in age-related functional decline. Here, we report that loss of murine erythrocyte-specific ADORA2B (eAdora2b-/-) accelerates early onset of age-related impairments in spatial learning, memory, and hearing ability. eAdora2b-/- mice display the early aging-like cellular and molecular features including the proliferation and activation of microglia and macrophages, elevation of pro-inflammatory cytokines, and attenuation of hypoxia-induced glycolytic gene expression to counteract hypoxia in the hippocampus (HIP), cortex, or cochlea. Hypoxia sufficiently accelerates early onset of cognitive and cochlear functional decline and inflammatory response in eAdora2b-/- mice. Mechanistically, erythrocyte ADORA2B-mediated activation of AMP-activated protein kinase (AMPK) and bisphosphoglycerate mutase (BPGM) promotes hypoxic and metabolic reprogramming to enhance production of 2,3-bisphosphoglycerate (2,3-BPG), an erythrocyte-specific metabolite triggering O2 delivery. Significantly, this finding led us to further discover that murine erythroblast ADORA2B and BPGM mRNA levels and erythrocyte BPGM activity are reduced during normal aging. Overall, we determined that erythrocyte ADORA2B-BPGM axis is a key component for anti-aging and anti-age-related functional decline.

Transmission of cerebral amyloid pathology by peripheral administration of misfolded Aß aggregates.

Previous reports showed that brain Aß amyloidosis can be induced in animal models by exogenous administration of pre-formed aggregates. To date, only intra-peritoneal and intra-venous administrations are described as effective means to peripherally accelerate brain Aß amyloidosis by seeding. Here, we show that cerebral accumulation of Aß can be accelerated after exposing mouse models of Alzheimer's disease (AD) to Aß seeds by different peripheral routes of administration, including intra-peritoneal and intra-muscular. Interestingly, animals receiving drops of brain homogenate laden with Aß seeds in the eyes were efficiently induced. On the contrary, oral administration of large quantities of brain extracts from aged transgenic mice and AD patients did not have any effect in brain pathology. Importantly, pathological induction by peripheral administration of Aß seeds generated a large proportion of aggregates in blood vessels, suggesting vascular transport. This information highlights the role of peripheral tissues and body fluids in AD-related pathological changes.

Peripheral Delivery of Neural Precursor Cells Ameliorates Parkinson's Disease-Associated Pathology.

: Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by loss of motor control due to a wide loss of dopaminergic neurons along the nigro-striatal pathway. Some of the mechanisms that contribute to this cell death are inflammation, oxidative stress, and misfolded alpha-synuclein-induced toxicity. Current treatments are effective at managing the early motor symptoms of the disease, but they become ineffective over time and lead to adverse effects. Previous research using intracerebral stem cell therapy for treatment of PD has provided promising results; however, this method is very invasive and is often associated with unacceptable side effects. In this study, we used an MPTP-injected mouse model of PD and intravenously administered neural precursors (NPs) obtained from mouse embryonic and mesenchymal stem cells. Clinical signs and neuropathology were assessed. Female mice treated with NPs had improved motor function and reduction in the neuroinflammatory response. In terms of safety, there were no tumorigenic formations or any detectable adverse effect after treatment. Our results suggest that peripheral administration of stem cell-derived NPs may be a promising and safe therapy for the recovery of impaired motor function and amelioration of brain pathology in PD.

Modifiable Risk Factors for Alzheimer's Disease.

Since first described in the early 1900s, Alzheimer's disease (AD) has risen exponentially in prevalence and concern. Research still drives to understand the etiology and pathogenesis of this disease and what risk factors can attribute to AD. With a majority of AD cases being of sporadic origin, the increasing exponential growth of an aged population and a lack of treatment, it is imperative to discover an easy accessible preventative method for AD. Some risk factors can increase the propensity of AD such as aging, sex, and genetics. Moreover, there are also modifiable risk factors-in terms of treatable medical conditions and lifestyle choices-that play a role in developing AD. These risk factors have their own biological mechanisms that may contribute to AD etiology and pathological consequences. In this review article, we will discuss modifiable risk factors and discuss the current literature of how each of these factors interplay into AD development and progression and if strategically analyzed and treated, could aid in protection against this neurodegenerative disease.

Impaired Peripheral Lymphatic Function and Cerebrospinal Fluid Outflow in a Mouse Model of Alzheimer's Disease.

Cerebrospinal fluid (CSF) outflow from the brain occurs through absorption into the arachnoid villi and, more predominantly, through meningeal and olfactory lymphatics that ultimately drain into the peripheral lymphatics. Impaired CSF outflow has been postulated as a contributing mechanism in Alzheimer's disease (AD). Herein we conducted near-infrared fluorescence imaging of CSF outflow into the peripheral lymph nodes (LNs) and of peripheral lymphatic function in a transgenic mouse model of AD (5XFAD) and wild-type (WT) littermates. CSF outflow was assessed from change in fluorescence intensity in the submandibular LNs as a function of time following bolus, an intrathecal injection of indocyanine green (ICG). Peripheral lymphatic function was measured by assessing lymphangion contractile function in lymphatics draining into the popliteal LN following intradermal ICG injection in the dorsal aspect of the hind paw. The results show 1) significantly impaired CSF outflow into the submandibular LNs of 5XFAD mice and 2) reduced contractile frequency in the peripheral lymphatics as compared to WT mice. Impaired CSF clearance was also evidenced by reduction of fluorescence on ventral surfaces of extracted brains of 5XFAD mice at euthanasia. These results support the hypothesis that lymphatic congestion caused by reduced peripheral lymphatic function could limit CSF outflow and may contribute to the cause and/or progression of AD.