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.

Keywords: Aging; Alzheimer’s disease; Amyloid-beta; Brain trauma; Neurodegeneration; Neurovascular unit.

Fig. 1

A–D: Brain tissue sections from a temporal cortex biopsy resected 12 h after severe TBI in a 39-year old subject from the University of Pittsburgh Brain Trauma Research Center (BTRC) were processed for immunohistochemistry using antibodies against the Aβ precursor protein (APP; polyclonal antibody anti-6, Athena), Aβ (antibody clone 10D5, Elan), and p-tau (antibody clone PHF-1, P. Davies, Albert Einstein College of Medicine). After severe TBI, APP accumulates in axons in the white matter (A), in cell bodies of pyramidal neurons in the grey matter (B), and Aβ deposits in diffuse Aβ plaques (C and inset). Rare profiles of phosphorylated tau (p-tau) immunoreactive fibers are detected in the gray matter (D; brown color is p-tau immunoreactivity, blue color is hematoxylin histological counterstain). E: Aβ1–42 peptide (Aβ42) concentrations (ELISA, Biosource) in cerebral spinal fluid (csf) from severe TBI patients (from the University of Pittsburgh BTRC; average age = 35.8 ± 15.7, range 17–65) at one, two, and three days after injury and from end-stage AD patients (from the University of Pittsburgh Alzheimer’s Disease Research Center; average age = 76.3 ± 10.2, range 63–91) are similarly reduced relative to levels in csf from cognitively normal control subjects (average age = 56.8 ± 14.5, range 25–78). *p < 0.05, **p < 0.01, ***p < 0.001 (Bonferroni multiple comparison post hoc test). Abbreviations: Aβ, amyloid-β; APP, Aβprecursor protein; p-tau, phosphorylated tau.

Fig. 2

Immunohistochemical analysis of hippocampus CA1 (A–F; I–L) and pericontusional somatosensory cortex (G, H) in human Aβ knock-in mice free of TBI (Naïve; A, C, E, G, I, K) and two weeks after severe controlled cortical impact injury (CCI; B, D, F, H, J, L). Tissue sections were immunoreacted with antibodies recognizing amyloid precursor protein (polyclonal anti-APP antibody CT695, Biosource; A, B), Aβ peptide (polyclonal anti-Aβ42 antibody, Millipore; C, D), Aβ oligomers (antibodies clones NU1/NU2, generous gift from W. Klein, Northwestern University; E, F and G, H), total tau (polyclonal anti-Tau antibody, Dako; I, J), and phosphorylated tau (biotinylated antibody clone AT8, Thermo, p-tau; K, L). Each marker is detected at low levels in naïve mice and prominently after CCI injury.

Fig. 3

Flow diagram illustrating concepts discussed in the current review, including the interaction between TBI and aging in relation to neurovascular dysfunction as precursors to, or risk factors for AD. In addition, genetic predisposition and epigenetic factors can influence pathways toward recovery or chronic pathology. Abbreviations: Aβ, amyloid-β; BBB, blood brain barrier; CBF, cerebral blood flow; CVD, cerebrovascular disease; NVU, neurovascular unit; TBI, traumatic brain injury.

Fig. 4

Confocal microscopy analyses of dendritic spines double immunolabeled using antibodies against spinophilin (polyclonal anti-spinophilin antibody, Millipore; green, A–D) and phalloidin (f-actin probe, Thermo; red, A–D) and presynaptic terminals immunolabeled with anti-synaptophysin antibody (polyclonal anti-synaptophysin antibody, Thermo; green, E–H) in the hippocampus of naïve (uninjured) wild type mice (line C57Bl/6, A, E) and naïve (uninjured) human Aβ (hAβ) knock-in mice (C, G) compared to CCI injured wild type mice (B, F) and hAβ mice (D,H) with 21 days survival. Blue fluorescence is DAPI counterstain. CCI injury results in loss of both spinophilin/phalloidin positive dendritic spines and synaptophysin positive presynaptic terminals, and the extent of this loss is greater in hAβ mice when compared to wild type mice.