Failure of clearance of proteins from the brain after traumatic brain injury

BACKGROUND

Cerebral amyloid angiopathy (CAA) is characterized by the deposition of Aβ40 in the walls of cortical arteries and represents a failure of clearance of Aβ along arteries (1). We have demonstrated that interstitial fluid and Aβ are eliminated from the brain parenchyma along basement membranes of capillaries and arteries and this process fails with increasing age and with possession of Apolipoprotein ε 4(APOE4) genotype (2-4). The motive force for efficient perivascular drainage appears to be provided by a combination of arterial tone, conformational changes of the arterial basement membranes and interstitial fluid pressure (5). As interstitial fluid pressure is related to cerebrospinal fluid dynamics, the drainage of Abeta may be affected by changes in the cerebrospinal fluid.

APOE4 is associated with poorer outcomes following traumatic brain injury (TBI), regardless of the severity of initial injury TBI is associated with increased risk of AD,73 and such a risk is more evident in patients with APOE4. Only 10% of APOE4 noncarriers with TBI have Aβ plaque pathology, whereas 35% and 100% of TBI patients with one or two APOE4 alleles, respectively, possess Aβ pathology.75 The poorer outcomes associated with ApoE4 might relate to its reduced ability to repair and remodel synapses and protect neurons upon injury compared with ApoE3.

There is evidence that Aβ deposits in the walls of cerebral arteries as soon as 48 hours after head injuries (6), suggesting that changes in the dynamics of cerebrospinal fluid lead to a failure of clearance of Abeta. TBI changes the structure of the extracellular matrix and this may impact upon the intramural periarterial drainage (IPAD) of soluble proteins and interstitial fluid from the brain, resulting in a perivascular deposition of proteins(7-9)However, it remains unknown how TBI and in particular CTE alters the drainage and the distribution of tau around the vessels. The hypothesis of this study is that the neurovascular disruption following TBI causes the accumulation of hyperphosphorylated tau in astrocytes surrounding the blood vessels.

The aim of this proposal is to investigate the characteristics of the morphological and functional disturbances in the wall of the blood vessels after TBI and associate them with neuropathological events leading to an alteration of the intramural periarterial drainage of tau and its deposition around the neurovascular unit. For this purpose, we will use the closed head injury model of TBI (which has been show to develop CTE) and will compare the results with those from post-mortem brains of CTE patients.

References

1. Weller RO, Subash M, Preston SD, Mazanti I, Carare RO. Perivascular Drainage of Amyloid-beta Peptides from the Brain and Its Failure in Cerebral Amyloid Angiopathy and Alzheimer’s Disease. Brain Pathol. 2008;18(2):253-66.
2. Carare RO, Bernardes-Silva M, Newman TA, Page AM, Nicoll JA, Perry VH, et al. Solutes, but not cells, drain from the brain parenchyma along basement membranes of capillaries and arteries: significance for cerebral amyloid angiopathy and neuroimmunology. NeuropatholApplNeurobiol. 2008;34(2):131-44.
3. Hawkes CA, Hartig W, Kacza J, Schliebs R, Weller RO, Nicoll JA, et al. Perivascular drainage of solutes is impaired in the ageing mouse brain and in the presence of cerebral amyloid angiopathy. Acta neuropathologica. 2011;121(4):431-43.
4. Hawkes CA, Sullivan PM, Hands S, Weller RO, Nicoll JA, Carare RO. Disruption of arterial perivascular drainage of amyloid-beta from the brains of mice expressing the human APOE epsilon4 allele. PloS one. 2012;7(7):e41636.
5. Schley D, Carare-Nnadi R, Please CP, Perry VH, Weller RO. Mechanisms to explain the reverse perivascular transport of solutes out of the brain. Journal of theoretical biology. 2006;238(4):962-74.
6. Leclercq PD, Murray LS, Smith C, Graham DI, Nicoll JA, Gentleman SM. Cerebral amyloid angiopathy in traumatic brain injury: association with apolipoprotein E genotype 3. J NeurolNeurosurgPsychiatry. 2005;76(2):229-33.
7. Jullienne A, Roberts JM, Pop V, Paul Murphy M, Head E, Bix GJ, et al. Juvenile traumatic brain injury induces long-term perivascular matrix changes alongside amyloid-beta accumulation. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism. 2014;34(10):1637-45.
8. Albargothy NJ, Johnston DA, MacGregor-Sharp M, Weller RO, Verma A, Hawkes CA, et al. Convective influx/glymphatic system: tracers injected into the CSF enter and leave the brain along separate periarterial basement membrane pathways. Acta neuropathologica. 2018.
9. Nimmo J, Johnston DA, Dodart JC, MacGregor-Sharp MT, Weller RO, Nicoll JAR, et al. Peri-arterial pathways for clearance of alpha-Synuclein and tau from the brain: Implications for the pathogenesis of dementias and for immunotherapy. Alzheimers Dement (Amst). 2020;12(1):e12070.