AGING IMPACT ON THE BRAIN TRANSCRIPTIONAL SIGNATURES

MaSSP – Jun 2021

ABG: Nguyen Bao Ngoc Diep, Pham Yen Giang, Pham Thi Ngoc Phuong, Van Phuong Trang
 REST is induced by oxidative and other forms of stress in the aging
Introduction: 
brain.
 Significant changes were found when comparing two groups of the
 The effects of time of the brain is still unclear to many scientist. In older populations (>85 and <80). The biggest change was the
this poster, we are going to look through two main changes of the downregulation of synaptic function genes/neuronal excitation
brain transcriptional signatures presented in the aging brain - genes. REST repressor function is upregulated in the brain in
decreased synaptic functions without neuronal cell loss and individuals with extended longevity, resulting in downregulation of
increased immune mechanisms. genes that mediate excitation and synaptic function.   
 The reduction of CX3CL1 and CX3CR1 in the process of
Increased Immune mechanism: regulating microglia cells led to the rising activation of microglia
in the older population mice after peripheral immune challenge.
Over activation of Microglia  The decreased CX3CL1 in the older mice brains may resulted in
Human a decline of microglia activation regulation after the LPS
Brain tissues were obtained postmortem from 34 individuals dying challenge. 
without clinical or pathological evidence of neurological disease.

Abstract:
 The decline of cognitive function has become one of the most
serious health problems of old age recently. Up to now, by different
research methods such as sequencing genes, RNAs of brain
samples,... they have specifically detected two major changes in the
brain transcriptional structure. First is synaptic transmission was
decreased by increased expression of the repressor element-1-
silencing transcription factor (REST) ​and decreased expression of
the tumor protein 73 (TP73). Second is the increased immune
system of the CNS leading to neuroinflammation due to increased
protein C1q and downregulation of the CX3CR1 gene in old age.
Decreased synaptic functions
without neuronal cell loss
Increased REST:  ΔNp73β after exposed to LY and Camptothectin (2 apoptotic factors)
 A gene silencing transcription factor that is widely expressed
during embryogenesis and is critical to elaboration of the neuronal
phenotype
 REST represses genes that promote cell death and AD pathology
and induces the expression of stress response genes.
 REST is neuroprotective in its nature, preventing and protecting
neurons from oxidative stress and amyloid-B protein toxicity
(lowering chances of AD).    BALB/c mice compared to adult (3–6 month) controls.
• REST expression is markedly higher in older adults than in
younger adults, especially clear in the brains of individuals at 60
or 70 years of age and older.   channels.
Decreased TP73 Most IL-1α + microglia cells are
 P73 is essential for postnatal development of additional CNS regulated in the brain of older
structures individuals (in the 6th and 7th
  decade of one’s lifetime)
Fig 1. (a) Comparison between brain
size of p73−/− versus p73+/+ animals
at ages ranging from P1 to P42. (b)
Comparison between olfactor buld
size and development of layers of Increased C1QA Conclusion
p73−/− versus p73+/+ animals at ages  Normal aging is associated with an increase in C1q protein (encoded  Decreased synaptic function and increased immune function
ranging from P1 to P42 by C1QA), particularly in certain regions of the brain that are are prevalent in most brain regions during aging.
 ΔNp73 is expressed by cortical neurons and rescues them from especially prone to degenerative diseases related to aging.  Decreasing synaptic function leads to decrease the generating
apoptosis  Less C1q, on the other hand, may confer some protection against and receiving signals among neurons without any neuronal
synapse loss and aging-related dysfunction of the hippocampus. loss. This underlies increased expression of REST since this
 The interaction between rs72788737 and age affects C1QA gene transcriptional factor prevents and downregulates those genes
expression. involved in mediate excitation and synaptic function, while
decreased expression of TP73 protein with its outstanding
regulation the expression of Cytochrome C in mitochondrial
Fig 2. Quantitation of (c) TUNEL and (d) caspase3 analysis cortical
function.
 The increase in brain immune activity is most associated with
neurons infected with recombinant adenoviruses expressing ΔNp73α or Microglial cells. Experiments show that Microglial activity is
over-activated in aging brains compared to young adult brains
(including mice and autopsy brains). The study of gene
  TAp73 is crucial to maintain mitochrondrial function by regulating expression shows that there are many genes that are specific
the expression of Cytochrome C for this cell's activity. We have taken two examples of CX3CR1
Fig 3 (g) Reduced oxygen
Decreased CX3CR1 gene and C1QA to clarify the influence of these genes.
 Fractalkine (CX3CL1) to fractalkine receptor (CX3CR1) interactions
comsumption in the lungs and
in the brain are involved in the modulation of microglial activation.
kidneys from wild-type and
 CX3CL1 protein was reduced in the brain of aged (18–22 month)
TAp73 knockout mice. (i) TAp73
References
knockout cells have reduced
basal ATP levels compared with  The microglia-specific neuroprotective • Lu, Tao et al. “REST and stress resistance in ageing and Alzheimer's disease.”
wild-type cells.  receptor for fractalkine (FKN), CX3CR1, Nature vol. 507,7493 (2014)
suppresses excessive immune • Zullo, Joseph M et al. “Regulation of lifespan by neural excitation and REST.”
Nature vol. 574,7778 (2019)
responses via microglia activation in • Rufini A, Niklison-Chirou MV, Inoue S, et al. TAp73 depletion accelerates aging
mice and rats. Signaling through the through metabolic dysregulation. Genes & Development. 2012
Fig 4. Reduced FKN ligand and its receptor, CX3CR1, in Sep;26(18):2009-2014..
basal ATP level microglia is reduced in aged brains, and • Christine D. Pozniak, Fanie Barnabé-Heider, Vladimir V. Rymar, Anna F. Lee,
Abbas F. Sadikot, Freda D. Miller J Neurosci. 2002 Nov 15; 22(22): 9800–
affects on close this reduction likely contributes to
or open state
9809. 
neurotoxic inflammation and results in • Qian Y, Chen X. Senescence regulation by the p53 protein family. Methods
of synaptic neurodegeneration. Mol Biol. 2013;965:37-61. doi: 10.1007/978-1-62703-239-1_3. PMID:
23296650; PMCID: PMC3784259.