The primordial small gaseous molecules, such as: NO, CO, H₂S and formaldehyde (FA) are present in the brains. Whether FA as well as the other molecules participates in brain functions is unclear. Recently, its pathophysiological functions have been investigated. Notably, under physiological conditions, learning activity induces a transient generation of hippocampal FA, which promotes memory formation by enhancing N-methyl-D-aspartate (NMDA)-currents. However, ageing leads to FA accumulation in brain for the dysregulation of FA metabolism; and excessive FA directly impairs memory by inhibiting NMDA-receptor. Especially, in Alzheimer's disease (AD), amyloid-beta (Aβ) accelerates FA accumulation by inactivating alcohol dehydrogenase-5; in turn, FA promotes Aβ oligomerization, fibrillation and tau hyperphosphorylation. Hence, there is a vicious circle encompassing Aβ assembly and FA generation. Even worse, FA induces Aβ deposition in the extracellular space (ECS), which blocks the medicines (dissolved in the interstitial fluid) flowing into the damaged neurons in the deep cortex. However, phototherapy destroys Aβ deposits in the ECS and restores ISF flow. Coenzyme Q10, which scavenges FA, was shown to ameliorate Aβ-induced AD pathological phenotypes, thus suggesting a causative relation between FA toxicity and AD. These findings suggest that the combination of these two methods is a promising strategy for treating AD.

Although Alzheimer’s disease (AD) was first described over 100 years ago, there is still no suitable biomarker for diagnosing AD in easily collectable samples (e.g., blood plasma, saliva, and urine). Here, we investigated the relationship between mor

Gaseous formaldehyde is an organic small molecule formed in the early stages of earth’s evolution. Although toxic in high concentrations, formaldehyde plays an important role in cellular metabolism and, unexpectedly, is found even in the healthy brain. However, its pathophysiological functions in the brain are unknown. Here, we report that under physiological conditions, spatial learning activity elicits rapid formaldehyde generation from mitochondrial sarcosine dehydrogenase (SARDH). We find that elevated formaldehyde levels facilitate spatial memory formation by enhancing N-methyl-D-aspartate (NMDA) currents via the C232 residue of the NMDA receptor, but that high formaldehyde concentrations gradually inactivate the receptor by cross-linking NR1 subunits to NR2B. We also report that in mice with aldehyde dehydrogenase-2 (ALDH2) knockout, formaldehyde accumulation due to hypofunctional ALDH2 impairs memory, consistent with observations of Alzheimerʼs disease patients. We also find that formaldehyde deficiency caused by mutation of the mitochondrialSARDHgene in children with sarcosinemia or in mice withSardhdeletion leads to cognitive deficits. Hence, we conclude that endogenous formaldehyde regulates learning and memory via the NMDA receptor.

Patients with type 2 diabetes mellitus (T2DM) often develop cognitive impairments and have an increased risk of developing Alzheimer's disease. Hyperglycemia is a major characteristic of T2DM, but how elevated glucose levels lead to cognitive decline remains elusive. Here, we report that patients with T2DM and mutations in the formaldehyde (FA)‐degrading enzyme aldehyde dehydrogenase 2 ( ALDH2) gene had higher levels of FA and more severe dementia. Injection of FA induced hyperglycemia and cognitive deficits in rats. Ablation of gene expression of ALDH2 , the main enzyme to oxidize FA, resulted in abnormally high levels of hippocampal FA, leading to hyperglycemia and cognitive impairments as well as potentiating streptozotocin‐induced diabetes development in ALDH2 knockout mice. We found that FA interacts with insulin to form FA‐insulin adducts, and these FA‐insulin adducts caused insulin deficiency, contributing to memory decline in diabetic rodent models. Reduction of FA by transgenic overexpression of human ALDH2 attenuates hyperglycemia and alleviates cognitive deficits in diabetic mouse models. These findings suggest that excess FA plays a critical role in mediating diabetes‐related dementia. Targeting FA and its metabolizing enzyme ALDH2 may be a valid approach for preventing and treating dementia in diabetes mellitus.—Tan, T., Zhang, Y., Luo, W., Lv, J., Han, C., Hamlin, J. N. R., Luo, H., Li, H., Wan, Y., Yang, X., Song, W., Tong, Z. Formaldehyde induces diabetes‐associated cognitive impairments. FASEB J. 32, 3669–3679 (2018). www.fasebj.org

Alzheimer's disease (AD), which is a prevailing type of dementia, presents a significant global health concern. The current therapies do not meet clinical expectations. Amyloid-beta (Aβ) has been found to induce endogenous formaldehyde (FA) accumulation by inactivating FA dehydrogenase (FDH); in turn, excessive FA triggers Aβ aggregation that eventually leads to AD onset. Hence, scavenging FA by astaxanthin (ATX, a strong exogenous antioxidant) may be pursued as a promising disease-modifying approach. Here, we report that liposomal nanoparticles coupled with PEG (PEG-ATX@NPs) could enhance water-solubility of ATX and alleviate cognitive impairments by scavenging FA and reducing Aβ deposition. To enable drug delivery to the brain, liposomes were used to encapsulate ATX and then coupled with PEG, which produced liposomal nanoparticles (PEGATX@NPs) with a diameter of <100 nm. The PEG-ATX@NPs reduced Aβ neurotoxicity by both degrading FA and reducing FA-induced Aβ assembly in vitro. Intraperitoneal administration of PEG-ATX@NPs in APPswe/PS1dE9 mice (APP/PS1, a familial model of AD), not only decreased the levels of brain FA and malondialdehyde (MDA, a typical product of oxidative stress), but also attenuated both intracellular Aβ oligomerization and extracellular Aβ-related senile plaque (SP) formation. These pathological changes were accompanied by rescued ability of spatial learning and memory. Collectively, PEG-ATX@NPs improved the water-solubility, bioavailability, and effectiveness of ATX. Thus, it has the potential to be developed as a safe and effective strategy for treating AD.