Exposure to the blood of young mice almost completely restored synaptic and neuronal protein levels in Alzheimer’s disease (AD) model mice, results from a study published in JAMA Neurology indicate.1
Previous studies have investigated the effects of exposing aged mice to the blood of young mice through heterochronic parabiosis – which involves surgically merging 2 animals of different ages – or via injection of blood plasma from the young mice to the older mice. For a control group, researchers compared tissues from the heterochronic pairs with those of 2 same-aged animals (isochronic pairs). Results of those experiments demonstrated that such exposure can reverse the “cognitive deficits observed with normal aging by increasing synaptic plasticity and hippocampal gene expression networks related to learning and memory and by improving vascular function,” the study authors wrote.2-4
In the present study, researchers at Stanford University School of Medicine and the San Francisco and San Diego campuses of the University of California examined the effects of young blood on aged amyloid precursor protein transgenic mice (APP mice) with beta-amyloid (Aβ) plaques, synaptic degeneration, and cognitive and behavioral impairment similar to those of AD patients. For a period of 5 weeks, 2 cohorts of APP mice that included either male mice aged 16-20 months or female mice aged 10-12 months, were merged via parabiosis or plasma injections with young mice that were 2-3 months old.
The findings revealed that synaptic and neuronal protein levels were restored to nearly normal levels in APP mice following young blood exposure through both parabiosis (synaptophysin P = .02; calbindin P = .02) and plasma injection (synaptophysin P < .001; calbindin P = .14). However, no change in Aβ plaques was observed, indicating that the restoration of proteins due to young blood exposure could occur despite elevated amyloid levels. It is notable that some human trials of medications targeting Aβ have not shown memory-preserving effects. Additionally, genome-wide microarray analysis revealed that many genes linked with key neuronal signaling pathways were restored after young blood exposure, and abnormal signaling of the AD-associated extracellular receptor kinase (ERK) was reversed (P = .05). Finally, working memory (P = .01) and associative memory improved in APP mice following young plasma injections (P = .02).
These results suggest that the administration of young plasma to AD patients could potentially ameliorate certain features of the disease, and studies testing the effects of this method on patients with AD are currently underway. “Although plasma administration is quite safe in humans and it would be possible to translate these findings to patients relatively quickly, pharmacological parameters and clinical end points will have to be established and safety in older patients needs to be demonstrated,” the authors concluded.
Disclosures: Dr Wyss-Coray reports that he is a co-founder and scientific advisor to Alkahest Inc. Drs Wyss-Coray, Middledorp, Villeda, and Luo are Alkahest Inc. shareholders and are named as inventors on a patent filed by Stanford University pertaining to young blood plasma.
- Middeldorp J, Lehallier B, Villeda SA, et al. Preclinical Assessment of Young Blood Plasma for Alzheimer Disease. JAMA Neurol. 2016; doi:10.1001/jamaneurol.2016.3185
- Villeda SA, Plambeck KE, Middeldorp J, et al. Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice. Nat Med. 2014; 20(6):659-663.
- Villeda SA, Luo J, Mosher KI, et al. The ageing systemic milieu negatively regulates neurogenesis and cognitive function. Nature. 2011; 477(7362): 90-94.
- Katsimpardi L, Litterman NK, Schein PA, et al. Vascular and neurogenic rejuvenation of the aging mouse brain by young systemic factors. Science. 2014; 344(6184):630-634.