Alzheimer's disease (AD) is an age-dependent neurodegenerative disease that causes progressive cognitive impairment. The initiation and progression of AD has been linked to cholesterol metabolism and inflammation, processes that can be modulated by liver x receptors (LXRs). We show here that endogenous LXR signaling impacts the development of AD-related pathology. Genetic loss of either Lxr␣ or Lxr␤ in APP/PS1 transgenic mice results in increased amyloid plaque load. LXRs regulate basal and inducible expression of key cholesterol homeostatic genes in the brain and act as potent inhibitors of inflammatory gene expression. Ligand activation of LXRs attenuates the inflammatory response of primary mixed glial cultures to fibrillar amyloid ␤ peptide (fA␤) in a receptordependent manner. Furthermore, LXRs promote the capacity of microglia to maintain fA␤-stimulated phagocytosis in the setting of inflammation. These results identify endogenous LXR signaling as an important determinant of AD pathogenesis in mice. We propose that LXRs may be tractable targets for the treatment of AD due to their ability to modulate both lipid metabolic and inflammatory gene expression in the brain.T he liver x receptors ␣ and ␤ (LXR␣/NR1H3 and LXR␤/ NR1H2, respectively) are oxysterol-activated nuclear receptors that play an important role in the control of cellular and whole-body cholesterol homeostasis (1-4). LXRs are also potent inhibitors of inflammatory responses in macrophages, pointing to an additional function for LXR signaling in immune regulation (5-11). The function of LXRs in the brain is not well understood. Ligand activation of LXRs promotes cholesterol efflux from glia (12, 13) and primary neurons (14), whereas mice deficient in expression of Lxr␣ and Lxr␤ develop marked accumulation of neutral lipids in the brain (15). Functionally, loss of LXR␤ leads to adult-onset motor neuron degeneration by the age of 7 months (16). The role of LXRs in human neurodegenerative diseases, however, remains largely unknown.Alzheimer's disease (AD) is an age-dependent neurodegenerative disease typified by progressive neuronal loss and cognitive impairment. AD is characterized by extraneuronal deposits of ␤-amyloid (A␤) fibrils (fA␤) (17) and intraneuronal tangles of hyperphosphorylated (18). The identification of rare mutations in the amyloid precursor protein (APP) and in presenilin genes (PS) in human AD is consistent with a central role for A␤ in AD pathogenesis (19). AD is a multifactorial disease, and inflammatory processes and cholesterol metabolism are among several factors that have been linked to its etiology.The AD brain exhibits prominent activation of innate immune responses. For example, elevated levels of inflammatory mediators can be measured in AD brains, and these are postulated to contribute to neuronal loss. The local inflammatory response is mediated by activated microglia and reactive astrocytes that surround the senile plaques (20,21). Interaction of microglia with fA␤ leads to their activation and the release of an arra...

Synaptic transmission is essential for nervous system function, and its dysfunction is a known major contributing factor to Alzheimer’s-type dementia. Antigen-specific immunochemical methods are able to characterize synapse loss in dementia through the quantification of various synaptic proteins involved in the synaptic cycle. These immunochemical methods applied to the study of Alzheimer’s disease (AD) brain specimens have correlated synaptic loss with particularly toxic forms of amyloid-β protein and have also established synapse loss as the best correlate of dementia severity. A significant but comparatively circumscribed amount of literature describes synaptic decline in other forms of dementia. Ischemic vascular dementia (IVD) is quite heterogeneous, and synapse loss in IVD seems to be variable among IVD subtypes, probably reflecting its variable neuropathologic correlates. Loss of synaptic protein has been identified in vascular dementia of the Binswanger type and Spatz-Lindenberg’s disease. Here we demonstrate a significant loss of synaptophysin density within the temporal lobe of frontotemporal dementia (FTD) patients.

Cerebral amyloid angiopathy (CAA) is common in elderly individuals, especially those affected with Alzheimer's disease. To investigate whether the presence of severe CAA (SCAA) in the brains of demented patients was associated with a higher burden of old microinfarcts than those with mild CAA (MCAA), 18 brains with SCAA were compared to 21 brains with MCAA. Immunohistochemistry for CD68 was employed to highlight old microinfarcts in tissue blocks from various brain regions. Old microinfarcts, manually counted by light microscopy, were present in 14 of 18 SCAA brains, and in 7 of 21 MCAA brains (P = 0.01, 2-tailed Fisher’s exact test). The average number of old microinfarcts across geographic regions in each brain ranged from 0 to 1.95 (mean rank 24.94, sum of ranks 449) in the SCAA group, and from 0 to 0.35 (mean rank 15.76, sum of ranks 331) in the MCAA group (P = 0.008, 2-tailed Mann-Whitney U test). Frequent old microinfarcts in demented individuals with severe CAA may contribute a vascular component to the cognitive impairment in these patients.

Microgliosis is prominent in Rasmussen's encephalitis (RE), a disease with severe seizure activity. However, it is unclear if microglial activation is similar with different histopathologic substrates. Iba1-immunolabelled microglial activation was assessed in neocortex from pediatric epilepsy surgery patients with RE (n=8), cortical dysplasia (CD; n=6) and tuberous sclerosis complex (TSC; n=6). Microglial reactivity was increased, in severely affected RE areas (29% labeling) compared with minimally affected areas of RE cases (15%) and cases of TSC (14%) and CD (12%). There was no qualitative association of Iba1 immunolabelling with the presence of CD8 + cytotoxic T-cells and no statistical association with clinical epilepsy variables, such as seizure duration or frequency. Iba1 appears to be an excellent marker for detecting extensive microglial activation in patients with RE. In addition, this study supports the notion that Iba1-labeled microglial activation is increased in patients with active RE, compared with cases of CD and TSC.

Nuclear Physics, Section A 830 (2009) 946c-956c. doi:10.1016/j.nuclphysa.2009.10.147Received by publisher: 0000-01-01Harvest Date: 2016-01-04 12:22:22DOI: 10.1016/j.nuclphysa.2009.10.147Page Range: 946c-956