Effects of tumor necrosis factor‐alpha central administration on hippocampal damage in rat induced by amyloid beta‐peptide (25–35)

Abstract

Male Wistar rats received unilateral intrahippocampal injections of 3 nmol (3.18 microg) aggregated Abeta(25-35), intracerebroventricular bilateral injections of 0.5 microg human recombinant TNFalpha or both (Abeta(25-35) + TNFalpha-treated animals). Seven days after the surgery brain sections were stained with cresyl violet (Nissl), for fragmented DNA (TUNEL), glial fibrillar acidic protein (GFAP) and isolectin B4-reactive microglia. In addition, caspase-3 activity in brain regions was measured fluorometrically. The morphology of the hippocampus after the injection of Abeta(25-35) or both Abeta(25-35) and TNFalpha (but not TNFalpha alone) showed cell loss in the CA1 pyramidal cell layer. The extension of neuronal degeneration measured in the CA1 field was significantly larger in Abeta(25-35)-treated groups compared to the contralateral hemisphere of both vehicle-treated controls and animals injected with TNFalpha alone. TNFalpha augmented the Abeta(25-35)-induced damage, significantly increasing the extension of degenerating area. Administration of Abeta(25-35) caused reactive gliosis in the ipsilateral hemisphere as demonstrated by upregulation of GFAP expression and the presence of hypertrophic astrocytes in the hippocampus. This effect was much more prominent in the hippocampi of rats treated with Abeta(25-35) + TNFalpha but absent after administration of TNFalpha alone. In both Abeta(25-35)-treated groups, the damaged area of the hippocampal CA1 field and lateral band of dentate gyrus displayed many darkly stained round isolectin B4-positive phagocyte-like microglial cells. Sparse TUNEL-positive nuclei were found in the hippocampi of rats treated with Abeta(25-35) alone or together with TNFalpha, but not in the control brain sections or in brain sections of TNFalpha-injected animals. The activity of caspase-3 increased significantly in the ipsilateral hippocampus after the injection of Abeta(25-35). Surprisingly, administration of TNFalpha into the cerebral ventricles prevented this Abeta(25-35)-induced increase in hippocampal caspase-3 activity. The results are discussed from the perspective of dual (neuroprotective and neurodestructive) roles of TNF in the brain.

Time-Course and Regional Analyses of the Physiopathological Changes Induced after Cerebral Injection of an Amyloid β Fragment in Rats

“…They demonstrated that A␤ and A␤ [25][26][27][28][29][30][31][32][33][34][35] induce apoptosis through caspase-dependent pathways. [41][42][43][44][45][46][47] In vivo, 1 week after A␤ [25][26][27][28][29][30][31][32][33][34][35] , an increase in caspase-3 activity in the hippocampus of rats 9 and increases in levels of pro-caspases 9, 12, and 3 in the hippocampus of mice 11 were observed. In the present study, we observed increases in pro-and cleaved forms for caspase-9 (mitochondrial stress marker) and caspase-12 (endoplasmic reticulum stress marker) in all structures except the hypothalamus.…”

“…Numbers of neurons in the different hippocampal fields were counted as described previously. 9,10,13 Counting was performed using a light microscope (Leica DMR). Digitized images were acquired using a 40ϫ objective and were analyzed with ImageJ software.…”

“…These models have led to highly pertinent pathomimetic observations and provide complementary approaches to the numerous transgenic mouse lines developed as AD models. In particular, at 1 week after A␤ [25][26][27][28][29][30][31][32][33][34][35] injection, reactive gliosis was observed in the rat hippocampus, 9 caspase-3 activity was induced in the hippocampus and cortex, 9 a reduction in the number of neurons was measured in the CA1 or CA3 hippocampal area, 9 -11 and significant oxidative stress was observed. [11][12][13] Nonetheless, this amyloid toxicity model remains controversial with respect to AD.…”

Neuroprotective properties of the innate immune system and bone marrow stem cells in Alzheimer's disease

“…However, it must be noted that the phenomenon only occurred when the production of the cytokines was unregulated or when high physiological concentrations of the cytokines were chronically administered in the CNS, and this has been supported by another study. 22 Indeed, other reports have shown that these cytokines can be neuroprotective during ischemia or cranial trauma when synthesized within physiological concentrations 23,24 while their overexpression causes neurodegeneration. 25 Moreover, it has been suggested that TNF-a is neuroprotective when it interacts with TNF-R2, whereas the cytokine induces neurodegeneration when it binds TNF-R1.…”

Cholinergic degeneration in early stages of Alzheimer’s disease: Loss of cholinergic phenotype or loss of cells?

“…Intrahippocampal injection of fibrillar Aβ induced direct lesions of the hippocampus, specifically CA1 field [48,49]. However, it also resulted in decreases in the medial septal ChAT and glutamate immunoreactive neurons as compared to controls.…”