Abnormalities of the Endosomal-Lysomal System in Alzheimer’s disease

Hamilton, Debra; Barnett, Jody L.; Paskevich, Peter A.; Nixon, Ralph A.

doi:10.1007/978-1-4613-0335-0_34

Cited by 36 publications

(25 citation statements)

References 36 publications

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“…That activation of gp330 expression may be involved in the neurodegenerative process is intriguing. There have already been reports of apoE uptake into endosomes (71,72) and studies on intracellular trafficking of apoE complexes (73). Additionally, there has been suggestion of A␤ enhancing the uptake of apoE (74).…”

Section: Discussionmentioning

confidence: 99%

Neuronal cell death in Alzheimer's disease correlates with apoE uptake and intracellular Abeta stabilization.

LaFerla¹,

Troncoso²,

Strickland³

et al. 1997

J. Clin. Invest.

155

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The brains of individuals with Alzheimer's disease (AD) are characterized by extracellular deposition of ␤ -amyloid protein (A ␤ ), intracellular neurofibrillary tangles, and loss of neurons. To study molecular markers associated with dying cells in the AD brain, in situ DNA labeling techniques were used to visualize cells with DNA fragmentation. We observed that intracellular accumulation of apolipoprotein E (apoE) is correlated with the detection of intracellular A ␤ -like immunoreactivity within the same cytoplasmic granules, suggesting that uptake of lipids may have stabilized the hydrophobic A ␤ protein within the cell. These apoEcontaining neurons also exhibit high expression of a cell surface receptor, gp330, which is known to bind apoE.

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Section: Discussionmentioning

confidence: 99%

Neuronal cell death in Alzheimer's disease correlates with apoE uptake and intracellular Abeta stabilization.

LaFerla¹,

Troncoso²,

Strickland³

et al. 1997

J. Clin. Invest.

155

View full text Add to dashboard Cite

show abstract

“…Angiotensin-converting enzyme is yet another metalloprotease that may play an important role in the pathogenesis of Alzheimer's disease and that has been shown to degrade Aβ in vitro [156] . Cathepsin D, an aspartyl protease localized within lysosomes and endosomes, was identified as a major Aβ-degrading enzyme in brain homogenates [157] , and its expression level in the brain is altered in Alzheimer's disease [158] .…”

Section: Aβ Degradationmentioning

confidence: 99%

Amyloid beta: structure, biology and structure-based therapeutic development

et al. 2017

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Amyloid beta peptide (Aβ) is produced through the proteolytic processing of a transmembrane protein, amyloid precursor protein (APP), by β-and γ-secretases. Aβ accumulation in the brain is proposed to be an early toxic event in the pathogenesis of Alzheimer's disease, which is the most common form of dementia associated with plaques and tangles in the brain. Currently, it is unclear what the physiological and pathological forms of Aβ are and by what mechanism Aβ causes dementia. Moreover, there are no efficient drugs to stop or reverse the progression of Alzheimer's disease. In this paper, we review the structures, biological functions, and neurotoxicity role of Aβ. We also discuss the potential receptors that interact with Aβ and mediate Aβ intake, clearance, and metabolism. Additionally, we summarize the therapeutic developments and recent advances of different strategies for treating Alzheimer's disease. Finally, we will report on the progress in searching for novel, potentially effective agents as well as selected promising strategies for the treatment of Alzheimer's disease. These prospects include agents acting on Aβ, its receptors and tau protein, such as small molecules, vaccines and antibodies against Aβ; inhibitors or modulators of β-and γ-secretase; Aβ-degrading proteases; tau protein inhibitors and vaccines; amyloid dyes and microRNAs.

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“…Some studies suggest that enhanced autophagy could be neuroprotective [31], while autophagic structures are frequently observed in increased numbers in dysfunctional or degenerating axons and dendrites in several neurodegenerative conditions, including AD [32], [33] and CJD [34]. In the electron microscope, autophagy appears in the form of numerous aberrant membrane structures, typically as double-membrane vacuole-like profiles in the axonal dystrophic or dendritic swellings.…”

Section: Discussionmentioning

confidence: 99%

Brain Region Specific Pre-Synaptic and Post-Synaptic Degeneration Are Early Components of Neuropathology in Prion Disease

et al. 2013

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Synaptic abnormalities, one of the key features of prion disease pathogenesis, gives rise to functional deficits and contributes to the devastating clinical outcome. The synaptic compartment is the first to succumb in several neurodegenerative diseases linked with protein misfolding but the mechanisms underpinning this are poorly defined. In our current study we document that a focal intrahippocampal injection of the mouse-adapted 22L scrapie strain produces a complex, region-specific pathology in the brain. Our findings reveal that early synaptic changes in the stratum radiatum of the hippocampus, identical to those observed with the ME7 strain, occur when 22L strain is introduced into the hippocampus. The pathology was defined by degenerating Type I pre-synaptic elements progressively enveloped by the post-synaptic density of the dendritic spine. In contrast, the pathology in the cerebellum suggested that dendritic disintegration rather than pre-synaptic abnormalities dominate the early degenerative changes associated with the Purkinje cells. Indeed, both of the major synaptic inputs into the cerebellum, which arise from the parallel and climbing fibers, remained intact even at late stage disease. Immunolabeling with pathway selective antibodies reinforced these findings. These observations demonstrate that neuronal vulnerability to pathological protein misfolding is strongly dependent on the structure and function of the target neurons.

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Abnormalities of the Endosomal-Lysomal System in Alzheimer’s disease

Cited by 36 publications

References 36 publications

Neuronal cell death in Alzheimer's disease correlates with apoE uptake and intracellular Abeta stabilization.

Neuronal cell death in Alzheimer's disease correlates with apoE uptake and intracellular Abeta stabilization.

Amyloid beta: structure, biology and structure-based therapeutic development

Brain Region Specific Pre-Synaptic and Post-Synaptic Degeneration Are Early Components of Neuropathology in Prion Disease

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