Lipolysaccharide-Induced Neuroinflammation Is Associated with Alzheimer-Like Amyloidogenic Axonal Pathology and Dendritic Degeneration in Rats

Abstract

Chronic neuroinflammation is thought to play an etiological role in Alzheimer’s disease (AD), which is characterized pathologically by amyloid and tau formation, as well as neuritic dystrophy and synaptic degeneration. The causal relationship between these pathological events is a topic of ongoing research and discussion. Recent data from transgenic AD models point to a tight spatiotemporal link between neuritic and amyloid pathology, with the obligatory enzyme for β-amyloid (Aβ) production, namely β-secretase-1 (BACE1), is overexpressed in axon terminals undergoing dystrophic change. However, the axonal pathology inherent with BACE1 elevation seen in transgenic AD mice may be secondary to increased soluble Aβ in these genetically modified animals. Here we explored the occurrence of the AD-like axonal and dendritic pathology in adult rat brain affected by LPS-induced chronic neuroinflammation. Unilateral intracerebral LPS injection induced prominent inflammatory response in glial cells in the ipsilateral cortex and hippocampal formation. BACE1 protein levels were elevated the ipsilateral hippocampal lysates in the LPS treated animals relative to controls. BACE1 immunoreactive dystrophic axons appeared in the LPS-treated ipsilateral cortex and hippocampal formation, colocalizing with increased β-amyloid precursor protein and Aβ antibody (4G8) immunolabeling. Quantitative Golgi studies revealed reduction of dendritic branching points and spine density on cortical layer III and hippocampal CA3 pyramidal neurons in the LPS-treated ipsilateral cerebrum. These findings suggest that Alzheimer-like amyloidogenic axonal pathology and dendritic degeneration occur in wildtype mammalian brain in partnership with neuroinflammation following LPS injection.

Aggregation of thrombin-derived C-terminal fragments as a previously undisclosed host defense mechanism

“…Interestingly, neutrophils have recently been implicated in the pathogenesis of amyloid deposits in AD of humans as well as in mouse AD models (31), highlighting the importance of peripheral innate immunity for amyloid formation. Thus, hypothetically, because both thrombin and neutrophils are increased in AD (32,33), high inflammatory activity could lead to degradation of thrombin and generation of amyloidogenic complexes.…”

Hydrocephalus compacted cortex and hippocampus and altered their output neurons in association with spatial learning and memory deficits in rats

“…The reduction of afferents in the hydrocephalus reported earlier (14) and indirectly in the present study (the reduction of synaptophysin level) could contribute to the pruning of dendritic spines that we observed. The mass compression effect of ventriculomegaly, brain ischemia (2) and inflammation (21,22) are likely additional factors to intensify the dendritic spine loss under hydrocephalus. In the present study, there was no apparent difference in the extent of the reductions of synaptophysin and PSD95 between the acute and chronic hydrocephalic cortices.…”

“…Immune responses are believed to be part of the kaolin-induced hydrocephalus in animals (14) and childhood hydrocephalus (19). Inflammation is known to affect dendritic spine dynamics (39), however a definitive effect on dendritic length remain controversial (4,21). The role of immune responses on the pathophysiology of neuronal dendrites in association with learning and memory deficits in hydrocephalus remains to be explored.…”

Chronic administration of a positive allosteric modulator at the α5-GABAA receptor reverses age-related dendritic shrinkage

“…Neuroinflammation and β-amyloid load have been extensively studied, especially in the context of Alzheimer's disease (30)(31)(32). However, more and more studies are showing that amyloid load is a normal process during aging (29), and the relationship between amyloid load and cognitive decline remains uncertain in healthy elderly (33,34).…”