Disordered APP metabolism and neurovasculature in trauma and aging: Combined risks for chronic neurodegenerative disorders

Abstract

Traumatic brain injury (TBI), advanced age, and cerebral vascular disease are factors conferring increased risk for late onset Alzheimer’s disease (AD). These conditions are also related pathologically through multiple interacting mechanisms. The hallmark pathology of AD consists of pathological aggregates of amyloid-β (Aβ) peptides and tau proteins. These molecules are also involved in neuropathology of several other chronic neurodegenerative diseases, and are under intense investigation in the aftermath of TBI as potential contributors to the risk for developing AD and chronic traumatic encephalopathy (CTE). The pathology of TBI is complex and dependent on injury severity, age-at-injury, and length of time between injury and neuropathological evaluation. In addition, the mechanisms influencing pathology and recovery after TBI likely involve genetic/epigenetic factors as well as additional disorders or comorbid states related to age and central and peripheral vascular health. In this regard, dysfunction of the aging neurovascular system could be an important link between TBI and chronic neurodegenerative diseases, either as a precipitating event or related to accumulation of AD-like pathology which is amplified in the context of aging. Thus with advanced age and vascular dysfunction, TBI can trigger self-propagating cycles of neuronal injury, pathological protein aggregation, and synaptic loss resulting in chronic neurodegenerative disease. In this review we discuss evidence supporting TBI and aging as dual, interacting risk factors for AD, and the role of Aβ and cerebral vascular dysfunction in this relationship. Evidence is discussed that Aβ is involved in cyto- and synapto-toxicity after severe TBI, and that its chronic effects are potentiated by aging and impaired cerebral vascular function. From a therapeutic perspective, we emphasize that in the fields of TBI- and aging-related neurodegeneration protective strategies should include preservation of neurovascular function.

The Amyloid-β Oligomer Hypothesis: Beginning of the Third Decade

“…TBI is a risk factor for AD [ 323 ] with AD developing in 55.5% of TBI patients [ 324 ]. Aβ pathology has been found to accumulate in the brain and CSF following TBI, including amyloid plaques [ 325 ] and AβOs [ 199, 323, 326–328 ].…”

Geriatric head injuries: impact and outcomes

“…This dramatically higher prevalence among older patients is hypothesized to result from the following factors: agerelated changes in vasculature and white matter rendering vessels more vulnerable to rupture and white matter tracts more susceptible to shear injury, weakened musculature in the neck and trunk; such that even ground-level falls are not well braced by the body, pre-existing conditions, and medications such as antithrombotics. 9,10,14 The outcome of ICP monitoring in elderly is controversial, with some studies in favour andothers showing no major benefit. 32,33 Anticoagulant agents such as warfarin are associated with increased mortality, but such is not observed with antiplatelet agents especially when surgical imtervemtion is required.…”

“…[3][4][5][6][7][8] Biologically, with aging, white matter and vasculature become more susceptible to injury. 9,10 Injury response mechanisms such as autophagy are dampened, and prevalence of pre-existing neurological or systemic comorbidities increases. 11 Elderly with TBI experience higher morbidity and mortality and slower recovery trajectories and have, on average, worse functional, cognitive, and psychosocial outcomes months or years post-injury than do younger patients.…”

Intravital imaging of vascular anomalies and extracellular matrix remodeling in orthotopic pancreatic tumors

“…The surgical procedure of mounting the imaging windows on the pancreas was as reported previously. 16,22 Briefly, the surgery was performed under Ketamine and Xylazine anesthesia (i.p injection; Ketamine 0.1 μl/g body weight; Xylazine 0.1 μl/g body weight) on feedback-controlled heating pad (FHC, Bowdoin, ME). The left dorsolateral side of the mice was shaved with a trimmer, cleaned thoroughly from remaining hair and disinfected with 70% ethanol.…”