Intraneuronal Aβ accumulation, amyloid plaques, and synapse pathology in Alzheimer's disease.

β-Amyloid (Aβ) plaques are a pathological hallmark of Alzheimer's disease (AD) and multiple lines of evidence have linked Aβ with AD. However, synapse loss is known as the best pathological correlate of cognitive impairment in AD, and intraneuronal Aβ accumulation has been shown to precede plaque pathology. The progression of Aβ accumulation to synapse loss and plaque formation remains incomplete. The objective is to investigate the progression of intraneuronal Aβ accumulation in the brain. To visualize and analyze the development of Aβ pathology we perform immunohistochemistry and immunofluorescence microscopy using antibodies against different Aβ conformations, synaptic proteins and structural neuronal proteins in brain tissue of AD transgenic mouse models. Our results show the intraneuronal onset of Aβ42 accumulation in AD mouse brains with aging. We observe an inverse correlation of Aβ and amyloid fibrils with structural proteins within neurites. Images reveal aggregated amyloid within selective pyramidal neurons, neurites and synapses in AD transgenic mice as plaques arise. The data support that Aβ42 accumulation and aggregation begin within AD-vulnerable neurons in the brain. Progressive intraneuronal Aβ42 aggregation disrupts the normal cytoarchitecture of neurites.

Capetillo-Zarate E ，Gracia L ，Tampellini D ，Gouras GK ... -  《-》

Intracellular amyloid-β accumulation in calcium-binding protein-deficient neurons leads to amyloid-β plaque formation in animal model of Alzheimer's disease.

Moon M ，Hong HS ，Nam DW ，Baik SH ，Song H ，Kook SY ，Kim YS ，Lee J ，Mook-Jung I ... -  《-》

[Involvement of beta-amyloid in the etiology of Alzheimer's disease].

Tomiyama T 《-》

Alzheimer's disease and amyloid: culprit or coincidence?

Alzheimer's disease (AD) is the largest unmet medical need in neurology today. This most common form of irreversible dementia is placing a considerable and increasing burden on patients, caregivers, and society, as more people live long enough to become affected. Current drugs improve symptoms but do not have profound neuroprotective and/or disease-modifying effects. AD is characterized by loss of neurons, dystrophic neurites, senile/amyloid/neuritic plaques, neurofibrillary tangles, and synaptic loss. Beta-amyloid (Aβ) peptide deposition is the major pathological feature of AD. Increasing evidence suggests that overexpression of the amyloid precursor protein and subsequent generation of the 39-43 amino acid residue, Aβ, are central to neuronal degeneration observed in AD patients possessing familial AD mutations, while transgenic mice overexpressing amyloid precursor protein develop AD-like pathology. Despite the genetic and cell biological evidence that supports the amyloid hypothesis, it is becoming increasing clear that AD etiology is complex and that Aβ alone is unable to account for all aspects of AD. The fact that vast overproduction of Aβ peptides in the brain of transgenic mouse models fails to cause overt neurodegeneration raises the question as to whether accumulation of Aβ peptides is indeed the culprit for neurodegeneration in AD. There is increasing evidence to suggest that Aβ/amyloid-independent factors, including the actions of AD-related genes (microtubule-associated protein tau, polymorphisms of apolipoprotein E4), inflammation, and oxidative stress, also contribute to AD pathogenesis. This chapter reviews the current state of knowledge on these factors and their possible interactions, as well as their potential for neuroprotection targets.

Skaper SD 《-》

Dispersible amyloid β-protein oligomers, protofibrils, and fibrils represent diffusible but not soluble aggregates: their role in neurodegeneration in amyloid precursor protein (APP) transgenic mice.

Soluble amyloid β-protein (Aβ) aggregates have been identified in the Alzheimer's disease (AD) brain. Dispersed Aβ aggregates in the brain parenchyma are different from soluble, membrane-associated and plaque-associated solid aggregates. They are in mixture with the extra- or intracellular fluid but can be separated from soluble proteins by ultracentrifugation. To clarify the role of dispersible Aβ aggregates for neurodegeneration we analyzed 2 different amyloid precursor protein (APP)-transgenic mouse models. APP23 mice overexpress human mutant APP with the Swedish mutation. APP51/16 mice express high levels of human wild type APP. Both mice develop Aβ-plaques. Dendritic degeneration, neuron loss, and loss of asymmetric synapses were seen in APP23 but not in APP51/16 mice. The soluble and dispersible fractions not separated from one another were received as supernatant after centrifugation of native forebrain homogenates at 14,000 × g. Subsequent ultracentrifugation separated the soluble, i.e., the supernatant, from the dispersible fraction, i.e., the resuspended pellet. The major biochemical difference between APP23 and APP51/16 mice was that APP23 mice exhibited higher levels of dispersible Aβ oligomers, protofibrils and fibrils precipitated with oligomer (A11) and protofibril/fibril (B10AP) specific antibodies than APP51/16 mice. These differences, rather than soluble Aβ and Aβ plaque pathology were associated with dendritic degeneration, neuron, and synapse loss in APP23 mice in comparison with APP51/16 mice. Immunoprecipitation of dispersible Aβ oligomers, protofibrils, and fibrils revealed that they were associated with APP C-terminal fragments (APP-CTFs). These results indicate that dispersible Aβ oligomers, protofibrils, and fibrils represent an important pool of Aβ aggregates in the brain that critically interact with membrane-associated APP C-terminal fragments. The concentration of dispersible Aβ aggregates, thereby, presumably determines its toxicity.

Rijal Upadhaya A ，Capetillo-Zarate E ，Kosterin I ，Abramowski D ，Kumar S ，Yamaguchi H ，Walter J ，Fändrich M ，Staufenbiel M ，Thal DR ... -  《-》