Age-Related Intraneuronal Elevation of αII-Spectrin Breakdown Product SBDP120 in Rodent Forebrain Accelerates in 3×Tg-AD Mice

Abstract

Spectrins line the intracellular surface of plasmalemma and play a critical role in supporting cytoskeletal stability and flexibility. Spectrins can be proteolytically degraded by calpains and caspases, yielding breakdown products (SBDPs) of various molecular sizes, with SBDP120 being largely derived from caspase-3 cleavage. SBDPs are putative biomarkers for traumatic brain injury. The levels of SBDPs also elevate in the brain during aging and perhaps in Alzheimer’s disease (AD), although the cellular basis for this change is currently unclear. Here we examined age-related SBDP120 alteration in forebrain neurons in rats and in the triple transgenic model of AD (3×Tg-AD) relative to non-transgenic controls. SBDP120 immunoreactivity (IR) was found in cortical neuronal somata in aged rats, and was prominent in the proximal dendrites of the olfactory bulb mitral cells. Western blot and densitometric analyses in wild-type mice revealed an age-related elevation of intraneuronal SBDP120 in the forebrain which was more robust in their 3×Tg-AD counterparts. The intraneuronal SBDP120 occurrence was not spatiotemporally correlated with transgenic amyloid precursor protein (APP) expression, β-amyloid plaque development, or phosphorylated tau expression over various forebrain regions or lamina. No microscopically detectable in situ activated caspase-3 was found in the nuclei of SBDP120-containing neurons. The present study demonstrates the age-dependent intraneuronal presence of an αII-spectrin cleavage fragment in mammalian forebrain which is exacerbated in a transgenic model of AD. This novel neuronal alteration indicates that impairments in membrane protein metabolism, possibly due to neuronal calcium mishandling and/or enhancement of calcium sensitive proteolysis, occur during aging and in transgenic AD mice.

iTRAQ-based Proteomic Analysis of APPSw,Ind Mice Provides Insights into the Early Changes in Alzheimer’s Disease

“…Spectrins were identified as one of the proteins deposited in Aβ plaques [ 54 , 55 ]. α-spectrin was shown to be cleaved by calpain and caspase-3 and its 120-kDa breakdown product was increased in the aged brains from both AD patients and 3×TgAD mice [ 56 - 59 ], and is therefore considered as a potential AD biomarker [ 60 ]. Recently, β-spectrin was also found to be cleaved by calpain and caspase under neurotoxic and traumatic brain-injury conditions [ 61 ].…”

Cerebellar ataxias: β‐III spectrin's interactions suggest common pathogenic pathways

“…It has been reported that a progressive increase in α‐II spectrin proteolysis (Cai et al . ; Hwang et al . ), a calcium‐dependent process linked to Purkinje cell toxicity (Mansouri et al .…”

Prospective clinical biomarkers of caspase-mediated apoptosis associated with neuronal and neurovascular damage following stroke and other severe brain injuries: Implications for chronic neurodegeneration

“…[ 127 128 ] In addition, caspase-3 activity is associated with proteolytic degradation of cytoskeletal proteins, such as αII-spectrin, further contributing to neuronal pathology in human TBI and animals models,[ 129 130 ] and preclinical evidence suggests that this pathology might be exacerbated by the presence of existing neurodegenerative disease. [ 131 ]…”

“…[ 130 ] Interestingly, increased levels of SBDP120 after experimental TBI were observed in the triple transgenic AD mice (3xTg-AD) compared to wild-type controls of the same background. [ 131 ] Clinical studies in severe TBI have confirmed utility of SBDP120 as a sensitive biomarker of caspase-3 activation exclusively associated with apoptotic cell death. [ 129 ] Other studies have confirmed the utility of SBDP145 and SBDP150 as highly useful biomarkers of calpain activation primarily associated with necrosis.…”

“…[ 153 244 245 ] Clinical and experimental data indicate that the increased levels of a specific caspase-3 proteolytic product, SBDP120, are associated axonal damage following TBI pathology in humans, and these processes are accelerated in AD-like animal models suggesting a possible link between mechanisms involved in chronic axonal damage in these disorders. [ 129 131 ]…”