Low-dose radiation decreases Lrrk2 levels in the striatum of large mammalian brains: New venues to treat Parkinson's disease?

INTRODUCTION: Among gene mutations and variants linked to an increased risk of PD, mutations of leucine-rich repeat kinase 2 gene (LRRK2) are among the most frequently associated with early- and late-onset PD. Clinical and neuropathological characteristics of idiopathic-PD (iPD) and LRRK2-PD are similar, and these similarities suggest that the pathomechanisms between these two conditions are shared. LRRK2 mutations determine a gain-of-function and yield higher levels of lrrk2 across body tissues, including brain. On another side, recent animal studies supported the potential use of low dose radiation (LDR) to modify the pathomechanisms of diseases such as Alzheimer's disease (AD). METHODS: We assessed if a single total-body LDR (sLDR) exposure in normal swine could alter expression levels of the following PD-associated molecules: alpha-synuclein (α-syn), phosphorylated-α-synuclein (pα-syn), parkin, tyrosine hydroxylase (th), lrrk2, phosphorylated-lrrk2 (pS935-lrrk2), and some LRRK2 substrates (Rab8a, Rab12) across different brain regions. These proteins were measured in frontal cortex, hippocampus, striatum, thalamus/hypothalamus, and cerebellum of 9 radiated (RAD) vs. 6 sham (SH) swine after 28 days from a sLDR of 1.79Gy exposure. RESULTS: Western Blot analyses showed lowered lrrk2 levels in the striatum of RAD vs. SH swine (p < 0.05), with no differences across the remaining brain regions. None of the other protein levels differed between RAD and SH swine in any examined brain regions. No lrrk2 and p-lrrk2 (S935) levels differed in the lungs of RAD vs. SH swine. CONCLUSIONS: These findings show a specific striatal lrrk2 lowering effect due to LDR and support the potential use of LDR to interfere with the pathomechanisms of PD.

Proteomic changes in the hippocampus of large mammals after total-body low dose radiation.

There is a growing interest in low dose radiation (LDR) to counteract neurodegeneration. However, LDR effects on normal brain have not been completely explored yet. Recent analyses showed that LDR exposure to normal brain tissue causes expression level changes of different proteins including neurodegeneration-associated proteins. We assessed the proteomic changes occurring in radiated vs. sham normal swine brains. Due to its involvement in various neurodegenerative processes, including those associated with cognitive changes after high dose radiation exposure, we focused on the hippocampus first. We observed significant proteomic changes in the hippocampus of radiated vs. sham swine after LDR (1.79Gy). Mass spectrometry results showed 190 up-regulated and 120 down-regulated proteins after LDR. Western blotting analyses confirmed increased levels of TPM1, TPM4, PCP4 and NPY (all proteins decreased in various neurodegenerative processes, with NPY and PCP4 known to be neuroprotective) in radiated vs. sham swine. These data support the use of LDR as a potential beneficial tool to interfere with neurodegenerative processes and perhaps other brain-related disorders, including behavioral disorders.

Low-dose brain radiation: lowering hyperphosphorylated-tau without increasing DNA damage or oncogenic activation.

Brain radiation has been medically used to alter the metabolism of cancerous cells and induce their elimination. Rarely, though, brain radiation has been used to interfere with the pathomechanisms of non-cancerous brain disorders, especially neurodegenerative disorders. Data from low-dose radiation (LDR) on swine brains demonstrated reduced levels of phosphorylated-tau (CP13) and amyloid precursor protein (APP) in radiated (RAD) versus sham (SH) animals. Phosphorylated-tau and APP are involved in Alzheimer's disease (AD) pathogenesis. We determined if the expression levels of hyperphosphorylated-tau, 3R-tau, 4R-tau, synaptic, intraneuronal damage, and DNA damage/oncogenic activation markers were altered in RAD versus SH swine brains. Quantitative analyses demonstrated reduced levels of AT8 and 3R-tau in hippocampus (H) and striatum (Str), increased levels of synaptophysin and PSD-95 in frontal cortex (FCtx), and reduced levels of NF-L in cerebellum (CRB) of RAD versus SH swine. DNA damage and oncogene activation markers levels did not differ between RAD and SH animals, except for histone-H3 (increased in FCtx and CRB, decreased in Str), and p53 (reduced in FCtx, Str, H and CRB). These findings confirm the region-based effects of sLDR on proteins normally expressed in larger mammalian brains and support the potential applicability of LDR to beneficially interfere against neurodegenerative mechanisms.

Reduction of pTau and APP levels in mammalian brain after low-dose radiation.

Brain radiation can occur from treatment of brain tumors or accidental exposures. Brain radiation has been rarely considered, though, as a possible tool to alter protein levels involved in neurodegenerative disorders. We analyzed possible molecular and neuropathology changes of phosphorylated-Tau (pTau), all-Tau forms, ß-tubulin, amyloid precursor protein (APP), glial fibrillary acidic protein (GFAP), ionized calcium binding adaptor molecule 1 (IBA-1), myelin basic protein (MBP), and GAP43 in Frontal Cortex (FC), Hippocampus (H) and Cerebellum (CRB) of swine brains following total-body low-dose radiation (1.79 Gy). Our data show that radiated-animals had lower levels of pTau in FC and H, APP in H and CRB, GAP43 in CRB, and higher level of GFAP in H versus sham-animals. These molecular changes were not accompanied by obvious neurohistological changes, except for astrogliosis in the H. These findings are novel, and might open new perspectives on brain radiation as a potential tool to interfere with the accumulation of specific proteins linked to the pathogenesis of various neurodegenerative disorders.

Arterial wall enhancement overlying carotid plaque on CT angiography correlates with symptoms in patients with high grade stenosis.

BACKGROUND AND PURPOSE: The degree of internal carotid artery (ICA) stenosis is an established primary risk factor for embolic stroke. Recent publications suggest that inflammatory features may also play an important role. Our purpose was to correlate acute neurological symptoms with either carotid artery wall enhancement or plaque calcification, on axial CT angiographic source images (CTA-SI) of patients with severe (>or=70%) ICA stenosis. METHODS: 75 consecutive patients with >or=70% ICA stenosis on CTA-SI were identified. Each case was classified as symptomatic (n=37) or asymptomatic (n=38), and as having either calcified or noncalcified plaque. The latter group was stratified into those with versus without arterial wall enhancement, measured in absolute and relative Hounsfield Units (HU). RESULTS: Calcified plaque was present in 39% (15/38) of the symptomatic patients and in 62% (23/37) of the asymptomatic patients (P=0.065). Of the 37 patients without calcified plaque, carotid wall enhancement was observed in 83% (19/23) of the symptomatic, but only in 57% (8/14) of the asymptomatic patients (P=0.041). When the "calcified plaque" and "no carotid wall enhancement" groups were pooled, versus the "carotid wall enhancement" group, enhancement was more likely in symptomatic patients (OR 3.625, CI 95% 1.3229 to 9.93, P=0.01 Fisher Exact test). CONCLUSIONS: In patients with severe ICA stenosis, additional stratification of stroke risk may be possible based on the presence of carotid wall enhancement on CTA-SI. Patients with carotid wall enhancement are more likely to be symptomatic, compared to those with either calcified plaque or no enhancement.

CNS glucagon-like peptide-1 receptors mediate endocrine and anxiety responses to interoceptive and psychogenic stressors.

Responses to stressors serve to adjust physiology and behavior to increase short-term survival at the potential expense of increasing susceptibility to disease over the long term. We show that glucagon-like peptide-1 (7-36) amide (GLP-1) increases levels of the stress-activated hormones ACTH and corticosterone when administered directly into the rat brain and increases levels of anxiety as measured by the elevated plus maze. The endocrine response is preferentially activated by GLP-1 administration in the paraventricular nucleus of the hypothalamus, whereas the anxiety response is preferentially activated by administration in the central nucleus of the amygdala. Furthermore, GLP-1 antagonists block increases in stress hormones associated with the toxin LiCl and both the endocrine and anxiety responses to vertical heights. Although diverse neural circuits must necessarily process disparate stressors, the current data implicate a role for the GLP-1 system as a critical mediator of multiple stress responses.