Evidence That Synaptically Released β-Amyloid Accumulates as Extracellular Deposits in the Hippocampus of Transgenic Mice

Lazarov, Orly; Lee, Michael; Peterson, Daniel A.; Sisodia, Sangram S.

doi:10.1523/jneurosci.22-22-09785.2002

Cited by 278 publications

(245 citation statements)

References 52 publications

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“…APP is transported along axons to presynaptic terminals where it accumulates at relatively high levels which can result in Aβ deposition at synpases 72 . One possible function of full-length APP is as a cell surface receptor that transduces signals within the cell in response to an extracellular ligand 73 .…”

Section: Boxmentioning

confidence: 99%

Pathways towards and away from Alzheimer's disease

Mattson

2004

Nature

2,753

2,058

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Slowly, but surely, Alzheimer's disease (AD) patients lose their memory, their cognitive abilities and even their personalities may change dramatically. These changes are due to the progressive dysfunction and death of nerve cells that are responsible for the storage and processing of information. While drugs can temporarily improve memory, at present there are no treatments that can stop or reverse the inexorable neurodegenerative process. But rapid progress towards understanding the cellular and molecular alterations that are responsible for the neuron's demise is increasing optimism that effective preventative and therapeutic strategies are in the offing.Alzheimer's disease (AD) is a neurodegenerative disorder that currently affects nearly 2% of the population in industrialized countries; the risk of AD dramatically increases in individuals beyond the age of 70 and it is predicted that the incidence of AD will triple within the next 50 years (www.alz.org). There can be other causes of memory loss and definitive diagnosis of AD therefore requires postmortem examination of the brain, which must contain sufficient numbers of "plaques" and "tangles" to qualify as AD 1, 2 . Plaques are extracellular deposits of fibrils and amorphous aggregates of amyloid β-peptide (Aβ); diffuse deposits of Aβ are also present in high amounts. Neurofibrillary tangles are intracellular fibrillar aggregates of the microtubule-associated protein tau which exhibit hyperphosphorylation and oxidative modifications. Plaques and tangles are present mainly in brain regions involved in learning and memory and emotional behaviors such as the entorhinal cortex, hippocampus, basal forebrain and amygdala. Brain regions with plaques typically exhibit reduced numbers of synapses, and neurites associated with the plaques are often damaged, suggesting that Aβ damages synapses and neurites. Neurons that employ glutamate or acetylcholine as neurotransmitters appear to be particularly affected, but neurons that produce serotonin and norepinephrine are also damaged. This review focuses on the molecular and cellular abnormalities that occur in the brain in AD, how they result in synaptic dysfunction and cell death, and how they can be counteracted. Central to the disease is altered proteolytic processing of the amyloid precursor protein (APP) resulting in the production and aggregation of neurotoxic forms of Aβ. Neurons that degenerate in AD exhibit increased oxidative damage, impaired energy metabolism and perturbed cellular calcium homeostasis; Aβ appears to be an important instigator of these abnormalities. Genetic and environmental factors can determine one's risk for and an understanding of these risk factors and how they modify the amyloid cascade is leading to the development of interventions for the prevention and treatment of AD that range from changes in diet and lifestyle, to vaccines and drugs.

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Section: Boxmentioning

confidence: 99%

Pathways towards and away from Alzheimer's disease

Mattson

2004

Nature

2,753

2,058

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“…7B). A major secretion site of Ab seems to be distal axons/synapses (Lazarov et al 2002;Sheng et al 2002), but recently it was reported that Ab can be secreted from axons and dendrites and can elicit local effects on neighboring neurons ( Fig. 7C; Wei et al 2010).…”

Section: Subcellular Sites Of G-secretase-mediated App Processingmentioning

confidence: 99%

“…Parallel studies in animal models and cell culture have linked APP transport, neuronal activity, and Ab metabolism. APP is axonally transported from the entorhinal cortex to the hippocampal formation via the perforant pathway (Buxbaum et al 1998a), and lesions of this pathway in transgenic mice overexpressing FAD-linked mutant APP and PS1 transgenes results in substantially less Ab deposition within the hippocampus (Lazarov et al 2002). Early studies showed that electrical depolarization increases the release of soluble APP-a in rat hippocampal brain slices (Nitsch et al 1993), and it appears that these effects are mediated by activation of muscarinic M1 acetylcholine receptors which leads to parallel decreases in Ab levels (Beach et al 2001;Hock et al 2003).…”

Section: Activity-dependent App Processingmentioning

confidence: 99%

Trafficking and Proteolytic Processing of APP

Haass¹,

Kaether²,

Wang³

et al. 2012

Cold Spring Harbor Perspectives in Medicine

893

892

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Accumulations of insoluble deposits of amyloid b-peptide are major pathological hallmarks of Alzheimer disease. Amyloid b-peptide is derived by sequential proteolytic processing from a large type I trans-membrane protein, the b-amyloid precursor protein. The proteolytic enzymes involved in its processing are named secretases. b-and g-secretase liberate by sequential cleavage the neurotoxic amyloid b-peptide, whereas a-secretase prevents its generation by cleaving within the middle of the amyloid domain. In this chapter we describe the cell biological and biochemical characteristics of the three secretase activities involved in the proteolytic processing of the precursor protein. In addition we outline how the precursor protein maturates and traffics through the secretory pathway to reach the subcellular locations where the individual secretases are preferentially active. Furthermore, we illuminate how neuronal activity and mutations which cause familial Alzheimer disease affect amyloid b-peptide generation and therefore disease onset and progression.

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“…Because CBF neurons are also an early target for NFT formation (77,78), a double-label PHFtau and choline acetyltransferase immunocytochemistry paradigm combined with single-cell mRNA analysis is a future direction that may help elucidate early alterations in these selectively vulnerable populations within the basal forebrain. Finally, the presence of extracellular SPs in the terminal fields of cholinergic innervation within the neocortex and hippocampus of AD brain suggests that alterations in the metabolism and transport of APP in CBF neurons may play a role in plaque formation (79,80), as evidenced by axotomy paradigms in mouse models of amyloid deposition where reduction of amyloid accumulation is observed on the side ipsilateral to the lesion (81)(82)(83).…”

Section: Single-cell Analysis In Ad: Choliner-gic Basal Forebrain (Cbmentioning

confidence: 99%

Single-Cell Gene Expression Analysis: Implications for Neurodegenerative and Neuropsychiatric Disorders

et al. 2004

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Technical and experimental advances in microaspiration techniques, RNA amplification, quantitative real-time polymerase chain reaction (qPCR), and cDNA microarray analysis have led to an increase in the number of studies of single-cell gene expression. In particular, the central nervous system (CNS) is an ideal structure to apply single-cell gene expression paradigms. Unlike an organ that is composed of one principal cell type, the brain contains a constellation of neuronal and noneuronal populations of cells. A goal is to sample gene expression from similar cell types within a defined region without potential contamination by expression profiles of adjacent neuronal subpopulations and noneuronal cells. The unprecedented resolution afforded by singlecell RNA analysis in combination with cDNA microarrays and qPCR-based analyses allows for relative gene expression level comparisons across cell types under different experimental conditions and disease states. The ability to analyze single cells is an important distinction from global and regional assessments of mRNA expression and can be applied to optimally prepared tissues from animal models as well as postmortem human brain tissues. This focused review illustrates the potential power of single-cell gene expression studies within the CNS in relation to neurodegenerative and neuropsychiatric disorders such as Alzheimer's disease (AD) and schizophrenia, respectively. KEY WORDS:Alzheimer's disease; cDNA microarray; cholinergic basal forebrain; dopamine receptors; expression profiling; protein phosphatases; RNA amplification; schizophrenia; single-cell microaspiration. Abbreviations (note the use of the NCBI-Unigene annotation): 3Rtau, three-repeat tau; 4Rtau, four-repeat tau; ACT, alpha-1-antichymotrypsin; ACTB, beta-actin; AGER, advanced glycosylation end product-specific receptor; APOE, apolipoprotein E; APP, amyloid-beta precursor protein; arc, activity regulated cytoskeletal-associated protein; BAX,

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Evidence That Synaptically Released β-Amyloid Accumulates as Extracellular Deposits in the Hippocampus of Transgenic Mice

Cited by 278 publications

References 52 publications

Pathways towards and away from Alzheimer's disease

Pathways towards and away from Alzheimer's disease

Trafficking and Proteolytic Processing of APP

Single-Cell Gene Expression Analysis: Implications for Neurodegenerative and Neuropsychiatric Disorders

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