Parallel age-associated changes in brain and plasma neuronal pentraxin receptor levels in a transgenic APP/PS1 rat model of Alzheimer's disease

Abstract

Neuronal pentraxin receptor (NPR) is a synaptic protein implicated in AMPA receptor trafficking at excitatory synapses. Since glutamate neurotransmission is disrupted in Alzheimer’s disease (AD), NPR levels measured from plasma represent a potential biomarker for synaptic dysfunction associated with AD. We sought to determine the relationship between AD pathology and brain and plasma NPR levels by examining age-associated NPR levels in these compartments in a transgenic APP/PS1 rat model of AD. NPR levels in cortical homogenate were similar in wild-type (Wt) and APP/PS1 rats at 3 months of age (prior to Aβ plaque deposition), but significantly increased in APP/PS1 rats by 9 and 18-20 months of age (after the onset of plaque deposition). These age-dependent differences were driven by proportional increases in NPR in membrane-associated cortical fractions. Genotype-related differences in NPR expression were also seen in the hippocampus, which exhibits significant Aβ pathology, but not in the cerebellum, which does not. Plasma analyses revealed increased levels of a 26 kDa NPR fragment in APP/PS1 rats relative to Wt rats by 18-20 months of age, which correlated with the levels of full-length NPR in cortex. Our findings indicate that cerebral accumulation of NPR and Aβ occurs with similar temporal and regional patterns in the APP/PS1 model, and suggest that a 26 kDa plasma NPR fragment may represent a peripheral biomarker of this process.

Dietary DHA supplementation in an APP/PS1 transgenic rat model of AD reduces behavioral and Aβ pathology and modulates Aβ oligomerization

“…In particular, marked deficits are seen by 18–20 months of age (Bilousova et al, 2015). Average swim latencies for the two treatment groups at 17–18 months of age across 10 days of training trials are shown in Figure 1A.…”

Neuronal pentraxin 1: A synaptic-derived plasma biomarker in Alzheimer's disease

“…NP1 negatively regulates mitochondrial function, transport and caspase activation through (Clayton et al, 2012) and negatively regulates excitatory synapse density (Figueiro-Silva et al, 2015). Since the expression of neuronal pentraxins is disrupted in AD brain and AD animal models (Abad et al, 2006, Bilousova et al, 2015, Cummings et al, 2017, Neuner et al, 2017, we investigated whether NP1 might serve as excitatory synapse derived plasma biomarker that is related to Aβ and/or apoE isoform effects.…”

The Role of Neuronal Pentraxin 2 (NP2) in Regulating Glutamatergic Signaling and Neuropathology

“…NP1 and its fragments are upregulated in the brain and plasma of 7-8-month-old E4FAD mice (a transgenic mouse model of familial AD using APOE4 genotype), in 4 month-old WT mice with induced αβ burden, and in the plasma of patients with mild cognitive impairment (Ma et al, 2018). Interestingly, NPR is upregulated in soluble cortical homogenate fractions of 3-9-month-old APP/PS1 rats, but not at 18-20 months (Bilousova et al, 2015). The suggestion is that the lack of soluble NPR in the late-stage animals was due to a degradation in TACE activity (Qian et al, 2016) leading to less cleaved NPR in the soluble preparations.…”

“…TACE (or ADAM17), the cleavage enzyme of NPR, is also able to act as an α-secretase for APP, resulting in a proposed neuroprotective by-product (Postina, 2012). TACE is also upregulated in AD (Skovronsky et al, 2001) but becomes inactive in the later stages of AD as the αβ burden increases (Bilousova et al, 2015). It could be that TACE is upregulated to combat the growing concentration of APP or in response to the increase in APP (Lüscher and Huber, 2010).…”

“…The pathology research supports the proposed mechanism and links NP2 expression to disease progression. Indeed, many neuronal pentraxins are being considered potential biomarkers for neurological disease (Yin et al, 2009;Bilousova et al, 2015;Xiao et al, 2017). Several of the diseases discussed herein have characteristic calcium and glutamate increases.…”