SPARCL1
SPARC-like protein 1 precursor (High endothelial venule protein) (Hevin) (MAST 9)
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Aging drives a progressive decline in cognition and decreases synapse numbers and synaptic function in the brain, thereby increasing the risk for neurodegenerative disease. Pioneering studies showed that introduction of blood from young mice into aged mice reversed age-associated cognitive impairments and increased synaptic connectivity in brain, suggesting that young blood contains specific factors that remediate age-associated decreases in brain function. However, whether such factors in blood from young animals act directly on neurons to enhance synaptic connectivity, or whether they act by an indirect mechanism remains unknown. Moreover, which factors in young blood mediate cognitive improvements in old mice is incompletely understood. Here, we show that serum extracted from the blood of young but not old mice, when applied to neurons transdifferentiated from human embryonic stem cells, directly increased dendritic arborization, augmented synapse numbers, doubled dendritic spine-like structures, and elevated synaptic [i]N[/i]-methyl-d-aspartate (NMDA) receptors, thereby increasing synaptic connectivity. Mass spectrometry revealed that thrombospondin-4 (THBS4) and SPARC-like protein 1 ([[SPARCL1]]) were enriched in serum from young mice. Strikingly, recombinant THBS4 and [[SPARCL1]] both increased dendritic arborization and doubled synapse numbers in cultured neurons. In addition, [[SPARCL1]] but not THBS4 tripled NMDA receptor-mediated synaptic responses. Thus, at least two proteins enriched in young blood, THBS4 and [[SPARCL1]], directly act on neurons as synaptogenic factors. These proteins may represent rejuvenation factors that enhance synaptic connectivity by increasing dendritic arborization, synapse formation, and synaptic transmission.
MeSH Terms
- Age Factors
- Aging
- Animals
- Calcium-Binding Proteins
- Cells, Cultured
- Extracellular Matrix Proteins
- Female
- Humans
- Male
- Mice
- Receptors, N-Methyl-D-Aspartate
- Synapses
- Synaptic Transmission
- Thrombospondins
Keywords
- NMDA receptors
- aging
- synapse
- synaptic transmission
- synaptogenesis
We recently reported that alpha-2 macroglobulin (A2M) is a biomarker of neuronal injury in Alzheimer's disease (AD) and identified a network of nine genes co-expressed with A2M in the brain. This network includes the gene encoding SPARCL1, a protein implicated in synaptic maintenance. Here, we examine whether SPARCL1 is associated with longitudinal changes in brain structure and function in older individuals at risk for AD in the Baltimore Longitudinal Study of Aging. Using data from the Gene-Tissue Expression Project, we first identified two single nucleotide polymorphisms (SNPs), rs9998212 and rs7695558, associated with lower brain SPARCL1 gene expression. We then analyzed longitudinal trajectories of cognitive performance in 591 participants who remained cognitively normal (average follow-up interval: 11.8 years) and 129 subjects who eventually developed MCI or AD (average follow-up interval: 9.4 years). Cognitively normal minor allele carriers of rs7695558 who developed incident AD showed accelerated memory loss prior to disease onset. Next, we compared longitudinal changes in brain volumes (MRI; n = 120 participants; follow-up = 6.4 years; 826 scans) and resting-state cerebral blood flow (rCBF; 15O-water PET; n = 81 participants; follow-up = 7.7 years; 664 scans) in cognitively normal participants. Cognitively normal minor allele carriers of rs9998212 showed accelerated atrophy in several global, lobar, and regional brain volumes. Minor allele carriers of both SNPs showed longitudinal changes in rCBF in several brain regions, including those vulnerable to AD pathology. Our findings suggest that SPARCL1 accelerates AD pathogenesis and thus link neuroinflammation with widespread changes in brain structure and function during aging.
MeSH Terms
- Aged
- Aged, 80 and over
- Aging
- Alzheimer Disease
- Brain
- Calcium-Binding Proteins
- Cerebrovascular Circulation
- Cognition Disorders
- Extracellular Matrix Proteins
- Female
- Humans
- Independent Living
- Longitudinal Studies
- Magnetic Resonance Imaging
- Male
- Middle Aged
- Neuropsychological Tests
- Polymorphism, Single Nucleotide
- Positron-Emission Tomography
Keywords
- Alzheimer’s disease
- magnetic resonance imaging
- positron emission tomography
- single nucleotidepolymorphism