The systemic environment: at the interface of aging and adult neurogenesis

Smith, Lucas K.; White, Charles; Villeda, Saul

doi:10.1007/s00441-017-2715-8

Cited by 58 publications

(48 citation statements)

References 77 publications

(144 reference statements)

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“…This hypothesis posits that neuroinflammation during aging is not a physiological defense reaction to a pathological process, but becomes pathogenic in itself (14)(15)(16)(17). Another widely shared idea is that age-related cognitive impairments result from decreased adult neurogenesis, although only a small percentage of neurons are actually generated by adult neurogenesis (18)(19)(20). A third hypothesis posits that aging is an intrinsic process in neurons, which as nonrenewable cells become incrementally less functional over the lifetime of an individual, thereby leading to a corresponding decrease in brain function (21).…”

mentioning

confidence: 99%

Specific factors in blood from young but not old mice directly promote synapse formation and NMDA-receptor recruitment

Gan

Südhof

2019

Proc. Natl. Acad. Sci. U.S.A.

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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 Nmethyl-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. aging | synaptogenesis | NMDA receptors | synaptic transmission | synapse N ormal aging drives a progressive decline in cognitive function and predisposes healthy individuals to neurodegenerative disorders. Once believed to arise substantially from neuronal cell death (1), age-induced cognitive decline is now generally thought to be due to a decrease in neuronal function (2, 3). Numerous studies in rodents and primates have shown that aging decreases the number of synapses and dendritic spines in cortex and reduces the length and arborization of dendrites (4-10). Moreover, in nonhuman primates, aging reduces the frequency of spontaneous excitatory postsynaptic events (11), impairs synaptic plasticity (2), and lowers expression of AMPA receptors (AMPARs) and N-methyl-D-aspartate receptors (NMDARs) (12, 13). Together, these findings suggest that a general loss of synaptic connectivity without concomitant changes in neuronal survival may underlie aging-induced memory impairments and cognitive decline.The molecular mechanisms that decrease synaptic connectivity and promote neurodegeneration during aging remain unclear. Several hypotheses have been advanced. One major hypothesis suggests that aging is driven by excessive neuroinflammation. This hypothesis posits that neuroinflammation during aging ...

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confidence: 99%

Specific factors in blood from young but not old mice directly promote synapse formation and NMDA-receptor recruitment

Gan

Südhof

2019

Proc. Natl. Acad. Sci. U.S.A.

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“…34 Similarly, there are clear differences in the cell composition and transcriptome between aged and adult neurogenic niches. 35 We did not detect any changes in SVZ neurogenesis in adult mice, indicating that loss of Cxcr5 affects neurogenesis in a region and age specific manner.…”

Section: Discussionmentioning

confidence: 54%

Loss of Cxcr5 alters neuroblast proliferation and migration in the aged brain

et al. 2020

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Neurogenesis, the production of new neurons from neural stem cells, dramatically decreases during aging concomitantly with increased inflammation both systemically and in the brain. However, the precise role of inflammation and whether local or systemic factors drive the neurogenic decline during aging is poorly understood. Here, we identify CXCR5/5/CXCL13 signaling as a novel regulator of neurogenesis in the aged brain. The chemokine Cxcl13 was found to be upregulated in the brain during aging. Loss of its receptor, Cxcr5, led to increased proliferation and decreased numbers of neuroblasts in the aged subventricular zone (SVZ), together with accumulation of neuroblasts in the rostral migratory stream and olfactory bulb (OB), without increasing the amount of new mature neurons in the OB. The effect on proliferation and migration was specific to neuroblasts and likely mediated through increased levels of systemic IL‐6 and local Cxcl12 expression in the SVZ. Our study raises the possibility of a new mechanism by which interplay between systemic and local alterations in inflammation regulates neurogenesis during aging.

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“…There is increasing evidence for blood-born elements influencing molecular, cellular, structural, and functional features of the brain in aging and in de-and regeneration in CNS diseases such as AD (Villeda et al, 2011(Villeda et al, , 2014Middeldorp et al, 2016;Smith et al, 2018). In this context, blood components of emerging interest are platelets.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, novel concepts consider that the brain is not an isolated organ but is strongly influenced by systemic factors, which might contribute to brain degeneration or alternatively function as protective and/or self-regenerative mechanisms to compensate CNS damages. Along this line, increasing evidence illustrates that blood components are contributing to brain aging (Villeda et al, 2011;Smith et al, 2018) and that components present in young blood might be developed as therapeutics to treat AD (Middeldorp et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

Platelets in Amyloidogenic Mice Are Activated and Invade the Brain

et al. 2020

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Alzheimer's disease (AD) is a neurodegenerative disease with a complex and not fully understood pathogenesis. Besides brain-intrinsic hallmarks such as abnormal deposition of harmful proteins, i.e., amyloid beta in plaques and hyperphosphorylated Tau in neurofibrillary tangles, blood-derived elements, in particular, platelets have been discussed to be involved in AD pathogenesis. The underlying mechanisms, however, are rather unexplored. Here, we investigate a potential role of platelets in an AD transgenic animal model with severe amyloid plaque formation, the APP-PS1 transgenic mice, and analyzed the presence, spatial location and activation status of platelets within the brain. In APP-PS1 mice, a higher number of platelets were located within the brain parenchyma, i.e., outside the cerebral blood vessels compared to WT controls. Such platelets were activated according to the expression of the platelet activation marker CD62P and to morphological hallmarks such as membrane protrusions. In the brain, platelets were in close contact exclusively with astrocytes suggesting an interaction between these two cell types. In the bloodstream, although the percentage of activated platelets did not differ between transgenic and age-matched control animals, APP-PS1 blood-derived platelets showed remarkable ultrastructural peculiarities in platelet-specific organelles such as the open canalicular system (OCS). This work urges for further investigations on platelets and their yet unknown functional roles in the brain, which might go beyond AD pathogenesis and be relevant for various age-related neurodegenerative diseases.

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The systemic environment: at the interface of aging and adult neurogenesis

Cited by 58 publications

References 77 publications

Specific factors in blood from young but not old mice directly promote synapse formation and NMDA-receptor recruitment

Specific factors in blood from young but not old mice directly promote synapse formation and NMDA-receptor recruitment

Loss of Cxcr5 alters neuroblast proliferation and migration in the aged brain

Platelets in Amyloidogenic Mice Are Activated and Invade the Brain

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