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Gene-environment interaction promotes Alzheimer's risk as revealed by synergy of repeated mild traumatic brain injury and mouse App knock-in.

ABSTRACT: There is a strong unmet need for translational progress towards Alzheimer's disease (AD) modifying therapy. Unfortunately, preclinical modeling of the disease has been disappointing, relying primarily on transgenic mouse overexpression of rare dominant mutations. Clinical manifestation of AD symptoms is known to reflect interaction between environmental and genetic risks. Mild traumatic brain injury (mTBI) is an environmental risk for dementia, including Alzheimer's, but there has been limited mechanistic analysis of mTBI contribution to AD. Here, we investigate the interplay between mTBI and Aβ precursor protein gene mutation in AD pathogenesis. We employed a knock-in (KI) model of AD that expresses the Aß-containing exons from human APP bearing the Swedish and Iberian mutations, namely App^NL-F/NL-F mice. Without environmental risk, this genetic variation yields minimal mouse symptomatology. Anesthetized 4-month-old KI mice and their age-matched wild type (WT) controls were subjected to repeated mild closed head injury (rmCHI), once daily for 14 days. Anesthetized, uninjured genotype- and age-matched mice were used as sham controls. At 3- and 8-months post-injury, amyloid-β, phospho-tau and Iba1 expression in the injured KI cortices were assessed. Our data reveal that rmCHI enhances accumulation of amyloid-β and hyperphosphorylated tau inclusions, as well as neuroinflammation in App^NL-F/NL-F mice. Furthermore, novel object recognition and Morris water maze tests demonstrated that rmCHI greatly exacerbates persistent cognitive deficits in APP^NL-F/NL-F mice. Therefore, study of gene-environment interaction demonstrates that combining risk factors provides a more robust model for AD, and that repeated mTBI substantially accelerates AD pathology in a genetically susceptible situation.

SUBMITTER: Chiasseu M

PROVIDER: S-EPMC7572902 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundExo70 is a subunit of the greater exocyst complex, a collection of proteins that oversees cellular membrane addition and polarized exocytosis by acting as a tethering intermediate between the plasma membrane and newly synthesized secretory vesicles. Although Exo70 function has been implicated in several developmental events including cytokinesis and the establishment of cell polarity, its role in neuropathologies is poorly understood. On the other hand, traumatic brain injury is the result of mechanical external force including contusion, fast acceleration, and expansive waves that produce temporal or permanent cognitive damage and triggers physical and psychosocial alterations including headache, memory problems, attention deficits, difficulty thinking, mood swings, and frustration. Traumatic brain injury is a critical health problem on a global scale, constituting a major cause of deaths and disability among young adults. Trauma-related cellular damage includes redistribution of N-methyl-D-aspartate receptors outside of the synaptic compartment triggering detrimental effects to neurons. The exocyst has been related to glutamate receptor constitutive trafficking/delivery towards synapse as well. This work examines whether the exocyst complex subunit Exo70 participates in traumatic brain injury and if it is redistributed among subcellular compartments RESULTS: Our analysis shows that Exo70 expression is not altered upon injury induction. By using subcellular fractionation, we determined that Exo70 is redistributed from microsomes fraction into the synaptic compartment after brain trauma. In the synaptic compartment, we also show that the exocyst complex assembly and its interaction with GluN2B are increased. Finally, we show that the Exo70 pool that is redistributed comes from the plasma membrane.ConclusionsThe present findings position Exo70 in the group of proteins that could modulate GluN2B synaptic availability in acute neuropathology like a traumatic brain injury. By acting as a nucleator factor, Exo70 is capable of redirecting the ensembled complex into the synapse. We suggest that this redistribution is part of a compensatory mechanism by which Exo70 is able to maintain GluN2B partially on synapses. Hence, reducing the detrimental effects associated with TBI pathophysiology.

Project description:BackgroundIndividuals who have experienced mild traumatic brain injuries (mTBIs) suffer from several comorbidities, including chronic pain. Despite extensive studies investigating the underlying mechanisms of mTBI-associated chronic pain, the role of inflammation in long-term pain after mTBIs is not fully elucidated. Given the shifting dynamics of inflammation, it is important to understand the spatial-longitudinal changes in inflammatory processes following mTBIs and their effects on TBI-related pain.MethodsWe utilized a recently developed transgenic caspase-1 luciferase reporter mouse model to monitor caspase-1 activation through a thinned skull window in the in vivo setting following three closed-head mTBI events. Organotypic coronal brain slice cultures and acutely dissociated dorsal root ganglion (DRG) cells provided tissue-relevant context of inflammation signal. Mechanical allodynia was assessed by mechanical withdrawal threshold to von Frey and thermal hyperalgesia withdrawal latency to radiant heat. Mouse grimace scale (MGS) was used to detect spontaneous or non-evoked pain. In some experiments, mice were prophylactically treated with MCC950, a potent small molecule inhibitor of NLRP3 inflammasome assembly to inhibit injury-induced inflammatory signaling. Bioluminescence spatiotemporal dynamics were quantified in the head and hind paws, and caspase-1 activation was confirmed by immunoblot. Immunofluorescence staining was used to monitor the progression of astrogliosis and microglial activation in ex vivo brain tissue following repetitive closed-head mTBIs.ResultsMice with repetitive closed-head mTBIs exhibited significant increases of the bioluminescence signals within the brain and paws in vivo for at least one week after each injury. Consistently, immunoblotting and immunofluorescence experiments confirmed that mTBIs led to caspase-1 activation, astrogliosis, and microgliosis. Persistent changes in MGS and hind paw withdrawal thresholds, indicative of pain states, were observed post-injury in the same mTBI animals in vivo. We also observed enhanced inflammatory responses in ex vivo brain slice preparations and DRG for at least 3 days following mTBIs. In vivo treatment with MCC950 significantly reduced caspase-1 activation-associated bioluminescent signals in vivo and decreased stimulus-evoked and non-stimulus evoked nociception.ConclusionsOur findings suggest that the inflammatory states in the brain and peripheral nervous system following repeated mTBIs are coincidental with the development of nociceptive sensitization, and that these events can be significantly reduced by inhibition of NLRP3 inflammasome activation.

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Gene-environment interaction promotes Alzheimer's risk as revealed by synergy of repeated mild traumatic brain injury and mouse App knock-in.

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