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 mitochondrial SARDH gene in children with sarcosinemia or in mice with Sardh deletion leads to cognitive deficits. Hence, we conclude that endogenous formaldehyde regulates learning and memory via the NMDA receptor.

Introduction Pharmacological therapies to treat Alzheimer's disease (AD) targeting “Aβ” have failed for over 100 years. Low levels of laser light can disassemble Aβ. In this study, we investigated the mechanisms that Aβ‐blocked extracellular space (ECS) induces memory disorders in APP/PS1 transgenic mice and addressed whether red light (RL) at 630 nm rescues cognitive decline by reducing Aβ‐disturbed flow of interstitial fluid (ISF). Methods We compared the heating effects on the brains of rats illuminated with laser light at 630, 680, and 810 nm for 40 minutes, respectively. Then, a light‐emitting diode with red light at 630 nm (LED‐RL) was selected to illuminate AD mice. The changes in the structure of ECS in the cortex were examined by fluorescent double labeling. The volumes of ECS and flow speed of ISF were quantified by magnetic resonance imaging. Spatial memory behaviors in mice were evaluated by the Morris water maze. Then, the brains were sampled for biochemical analysis. Results RL at 630 nm had the least heating effects than other wavelengths associated with ~49% penetration ratio into the brains. For the molecular mechanisms, Aβ could induce formaldehyde (FA) accumulation by inactivating FA dehydrogenase. Unexpectedly, in turn, FA accelerated Aβ deposition in the ECS. However, LED‐RL treatment not only directly destroyed Aβ assembly in vitro and in vivo but also activated FA dehydrogenase to degrade FA and attenuated FA‐facilitated Aβ aggregation. Subsequently, LED‐RL markedly smashed Aβ deposition in the ECS, recovered the flow of ISF, and rescued cognitive functions in AD mice. Discussion Aβ‐obstructed ISF flow is the direct reason for the failure of the developed medicine delivery from superficial into the deep brain in the treatment of AD. The phototherapy of LED‐RL improves memory by reducing Aβ‐blocked ECS and suggests that it is a promising noninvasive approach to treat AD.

Background Morning urine formaldehyde concentrations could predict the severe degree of dementia in patients with post-stroke dementia and Alzheimer’s disease. However, the routinely available technique of high-performance liquid chromatography (HPLC) for detecting urine formaldehyde requires expensive and sophisticated equipment. Methods We established a fluorescence spectrophotometric method by using a formaldehyde-specific fluorescent probe-NaFA (λex/em = 430/543 nm). As a standard reference method, the same batch of urine samples was analysed by HPLC with a fluorescence detector (λex/em = 346/422 nm). Then we compared the limits of detection and the limits of quantization detected by these two methods and addressed the relationship between urine formaldehyde and human cognitive ability. The Mini-Mental State Examination (MMSE), Clinical Dementia Rating and Activities of Daily Living scale were used to evaluate cognition function in 30 Alzheimer’s disease patients and 52 healthy age-matched controls. Results Limits of detection and limits of quantization (1.27 and 2.48 μM) of the NaFA probe method were more accurate than Fluo-HPLC (1.52 and 2.91 μM). There was no difference in the detected formaldehyde values within day and day-to-day. Notably, only 3/82 urine formaldehyde concentrations detected by NaFA probe were below zero, while 12/82 of the values analysed by Fluo-HPLC were abnormal. More importantly, there were negatively correlated between urine formaldehyde concentrations detected by NaFA probe and MMSE scores, but positively correlated with Clinical Dementia Rating scores in Alzheimer’s disease patients. Conclusions This detecting urine formaldehyde method by NaFA probe was more rapid, sensitive and accurate than Fluo-HPLC.