Disruption of neocortical histone H3 homeostasis by soluble Aß: implications for Alzheimer's disease.

Amyloid-ß peptide (Aß) fragment misfolding may play a crucial role in the progression of Alzheimer's disease (AD) pathophysiology as well as epigenetic mechanisms at the DNA and histone level. We hypothesized that histone H3 homeostasis is disrupted in association with the appearance of soluble Aß at an early stage in AD progression. We identified, localized, and compared histone H3 modifications in multiple model systems (neural-like SH-SY5Y, primary neurons, Tg2576 mice, and AD neocortex), and narrowed our focus to investigate 3 key motifs associated with regulating transcriptional activation and inhibition: acetylated lysine 14, phosphorylated serine 10 and dimethylated lysine 9. Our results in vitro and in vivo indicate that multimeric soluble Aß may be a potent signaling molecule indirectly modulating the transcriptional activity of DNA by modulating histone H3 homeostasis. These findings reveal potential loci of transcriptional disruption relevant to AD. Identifying genes that undergo significant epigenetic alterations in response to Aß could aid in the understanding of the pathogenesis of AD, as well as suggesting possible new treatment strategies.

Age-dependent neuroplasticity mechanisms in Alzheimer Tg2576 mice following modulation of brain amyloid-ß levels.

The objective of this study was to investigate the effects of modulating brain amyloid-ß (Aß) levels at different stages of amyloid pathology on synaptic function, inflammatory cell changes and hippocampal neurogenesis, i.e. processes perturbed in Alzheimer's disease (AD). Young (4- to 6-month-old) and older (15- to 18-month-old) APP(SWE) transgenic (Tg2576) mice were treated with the AD candidate drug (+)-phenserine for 16 consecutive days. We found significant reductions in insoluble Aß1-42 levels in the cortices of both young and older transgenic mice, while significant reductions in soluble Aß1-42 levels and insoluble Aß1-40 levels were only found in animals aged 15-18 months. Autoradiography binding with the amyloid ligand Pittsburgh Compound B ((3)H-PIB) revealed a trend for reduced fibrillar Aß deposition in the brains of older phenserine-treated Tg2576 mice. Phenserine treatment increased cortical synaptophysin levels in younger mice, while decreased interleukin-1ß and increased monocyte chemoattractant protein-1 and tumor necrosis factor-alpha levels were detected in the cortices of older mice. The reduction in Aß1-42 levels was associated with an increased number of bromodeoxyuridine-positive proliferating cells in the hippocampi of both young and older Tg2576 mice. To determine whether the increased cell proliferation was accompanied by increased neuronal production, the endogenous early neuronal marker doublecortin (DCX) was examined in the dentate gyrus (DG) using immunohistochemical detection. Although no changes in the total number of DCX(+)-expressing neurons were detected in the DG in Tg2576 mice at either age following (+)-phenserine treatment, dendritic arborization was increased in differentiating neurons in young Tg2576 mice. Collectively, these findings indicate that reducing Aß1-42 levels in Tg2576 mice at an early pathological stage affects synaptic function by modulating the maturation and plasticity of newborn neurons in the brain. In contrast, lowering Aß levels in Tg2576 mice when Aß plaque pathology is prominent mainly alters the levels of proinflammatory cytokines and chemokines.

Characterization of the brain ß-amyloid isoform pattern at different ages of Tg2576 mice.

BACKGROUND: Although genetic and biochemical studies have suggested a cardinal role for ß-amyloid (Aß) in Alzheimer's disease, the underlying mechanism(s) of how Aß induces neurodegeneration is still unclear. Our objective was to investigate the consequences of Aß, especially on tau phosphorylation at specific epitopes important for Alzheimer's disease. METHODS: We used cortices from Tg2576 mice at 7 days to 15 months of age. RESULTS: MALDI-TOF MS revealed an age-dependent shift in the Aß isoform pattern. Young animals displayed high cortical levels of the shorter Aß isoforms (Aß1-16 and Aß1-17) compared to 15-month-old Tg2576 mice which mainly expressed Aß1-40 and Aß1-42. The Aß1-42 showed an age-dependent increase, whereas total Aß1-40 levels remained constant. The highest levels of TBS-soluble Aß oligomers were found at 90 days of age. Brain Aß build-up did not affect the phosphorylation of tau at the epitopes investigated. CONCLUSIONS: This study provides new information about age-dependent Aß isoforms and oligomers as well as their effect on site-specific tau phosphorylation in this transgenic mouse model. Our observations suggest that the different human Aß isoforms do not directly cause increased tau phosphorylation and that the cognitive deficits seen in this mouse model are only related to the Aß overexpression.

Positron emission tomography imaging and clinical progression in relation to molecular pathology in the first Pittsburgh Compound B positron emission tomography patient with Alzheimer's disease.

The accumulation of ß-amyloid in the brain is an early event in Alzheimer's disease. This study presents the first patient with Alzheimer's disease who underwent positron emission tomography imaging with the amyloid tracer, Pittsburgh Compound B to visualize fibrillar ß-amyloid in the brain. Here we relate the clinical progression, amyloid and functional brain positron emission tomography imaging with molecular neuropathological alterations at autopsy to gain new insight into the relationship between ß-amyloid accumulation, inflammatory processes and the cholinergic neurotransmitter system in Alzheimer's disease brain. The patient underwent positron emission tomography studies with (18)F-fluorodeoxyglucose three times (at ages 53, 56 and 58 years) and twice with Pittsburgh Compound B (at ages 56 and 58 years), prior to death at 61 years of age. The patient showed a pronounced decline in cerebral glucose metabolism and cognition during disease progression, while Pittsburgh Compound B retention remained high and stable at follow-up. Neuropathological examination of the brain at autopsy confirmed the clinical diagnosis of pure Alzheimer's disease. A comprehensive neuropathological investigation was performed in nine brain regions to measure the regional distribution of ß-amyloid, neurofibrillary tangles and the levels of binding of (3)H-nicotine and (125)I-α-bungarotoxin to neuronal nicotinic acetylcholine receptor subtypes, (3)H-L-deprenyl to activated astrocytes and (3)H-PK11195 to microglia, as well as butyrylcholinesterase activity. Regional in vivo (11)C-Pittsburgh Compound B-positron emission tomography retention positively correlated with (3)H-Pittsburgh Compound B binding, total insoluble ß-amyloid, and ß-amyloid plaque distribution, but not with the number of neurofibrillary tangles measured at autopsy. There was a negative correlation between regional fibrillar ß-amyloid and levels of (3)H-nicotine binding. In addition, a positive correlation was found between regional (11)C-Pittsburgh Compound B positron emission tomography retention and (3)H-Pittsburgh Compound B binding with the number of glial fibrillary acidic protein immunoreactive cells, but not with (3)H-L-deprenyl and (3)H-PK-11195 binding. In summary, high (11)C-Pittsburgh Compound B positron emission tomography retention significantly correlates with both fibrillar ß-amyloid and losses of neuronal nicotinic acetylcholine receptor subtypes at autopsy, suggesting a closer involvement of ß-amyloid pathology with neuronal nicotinic acetylcholine receptor subtypes than with inflammatory processes.

Early changes in Abeta levels in the brain of APPswe transgenic mice--implication on synaptic density, alpha7 neuronal nicotinic acetylcholine- and N-methyl-D-aspartate receptor levels.

Tg 2576 (APPswe) mice develop age-related amyloid deposition as well as behavioural- and electrophysiological changes in the brain. In this study, APPswe mice were investigated from 7 to 90 days of age. We observed high Abeta levels in the cortex of APPswe mice at 7 days of age, suggesting that these mice produce Abeta from birth. A positive correlation between Abeta and synaptophysin levels, followed by changes in ERK MAPK activity, indicated that Abeta causes altered synaptic function and an increase in the number of synaptic terminals. In addition, alterations in [(125)I]alphabungarotoxin- and [(3)H]MK-801 binding sites were also observed in APPswe mice compared to controls. In conclusion, over-expression of Abeta early in life causes changes in synaptophysin levels and number of [(125)I]alphabungarotoxin- and [(3)H]MK-801 binding sites. The results may provide important information about the onset and consequences of Abeta pathology in this transgenic mouse model.