The Role of Amyloid-Beta Derived Diffusible Ligands (ADDLs) in Alzheimers Disease

Catalano, Susan M.; Dodson, Elizabeth Chen; Henze, Darrell A.; Joyce, Joseph G.; Krafft, Grant A.; Kinney, Gene G.

doi:10.2174/156802606776743066

Cited by 102 publications

(74 citation statements)

References 118 publications

(167 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Of these structures, oligomers are believed to be the most neurotoxic and important in the development of disease (3,8,9). Thus, any strategies to reduce amyloid-related phenotypes must avoid producing toxic oligomers from relatively benign structures, such as fibrils.…”

Section: Discussionmentioning

confidence: 99%

Heat Shock Proteins 70 and 90 Inhibit Early Stages of Amyloid β-(1–42) Aggregation in Vitro

Evans

Wisén

Gestwicki

2006

Journal of Biological Chemistry

340

304

View full text Add to dashboard Cite

Alzheimer disease is a neurological disorder that is characterized by the presence of fibrils and oligomers composed of the amyloid ␤ (A␤) peptide. In models of Alzheimer disease, overexpression of molecular chaperones, specifically heat shock protein 70 (Hsp70), suppresses phenotypes related to A␤ aggregation. These observations led to the hypothesis that chaperones might interact with A␤ and block self-association. However, although biochemical evidence to support this model has been collected in other neurodegenerative systems, the interaction between chaperones and A␤ has not been similarly explored. Here, we examine the effects of Hsp70/40 and Hsp90 on A␤ aggregation in vitro. We found that recombinant Hsp70/40 and Hsp90 block A␤ self-assembly and that these chaperones are effective at substoichiometric concentrations (ϳ1:50). The antiaggregation activity of Hsp70 can be inhibited by a nonhydrolyzable nucleotide analog and encouraged by pharmacological stimulation of its ATPase activity. Finally, we were interested in discerning what type of amyloid structures can be acted upon by these chaperones. To address this question, we added Hsp70/40 and Hsp90 to pre-formed oligomers and fibrils. Based on thioflavin T reactivity, the combination of Hsp70/40 and Hsp90 caused structural changes in oligomers but had little effect on fibrils. These results suggest that if these chaperones are present in the same cellular compartment in which A␤ is produced, Hsp70/40 and Hsp90 may suppress the early stages of self-assembly. Thus, these results are consistent with a model in which pharmacological activation of chaperones might have a favorable therapeutic effect on Alzheimer disease.The amyloid diseases are a collection of protein misfolding disorders associated with the formation of distinctive fibrils (reviewed in Refs. 1-5). Alzheimer disease is one of the most common amyloid diseases, and it is characterized by fibrils composed of A␤, 2 a 39 -43-amino acid proteolytic fragment of the amyloid precursor protein (reviewed in Ref. 6). Upon release from amyloid precursor protein, A␤ becomes enriched in ␤-sheet structure and acquires the propensity to self-assemble (7). Initial theories to explain the pathology of AD focused on the involvement of the visually striking fibrils, but more recent evidence has strongly supported a role for soluble oligomers (reviewed in Refs. 3 and 8 -10). A␤ oligomers can be prepared in vitro (11,12), biosynthesized by cultured cells (13,14), or collected from AD tissues (15), and in all cases, these structures are highly neurotoxic. Despite these important observations, numerous questions about the basis of disease are unanswered. For example, although there is active research in this area (8,11,16), the number of A␤ monomers present in an oligomer has not been fully described. Moreover, the subcellular site(s) of oligomer production and the conditions that lead to their assembly are still debated; fibrils are found in extracellular space, but there is growing evidence that oligomers may be pr...

show abstract

Section: Discussionmentioning

confidence: 99%

Heat Shock Proteins 70 and 90 Inhibit Early Stages of Amyloid β-(1–42) Aggregation in Vitro

Evans

Wisén

Gestwicki

2006

Journal of Biological Chemistry

340

304

View full text Add to dashboard Cite

show abstract

“…Lyophilized A␤(1-42),5-TMR (AnaSpec) that had been resuspended in 1,1,1,3,3,3-hexafluoro-2-propanol were used to prepare oA␤ 1-42 -TMR by diluting 5 mM A␤(1-42),5-TMR in Me 2 SO to a concentration of 100 M in HEPES buffer, pH 7.4. The solution was immediately vortexed and sonicated for 2 min and then incubated at 4°C for 24 h (Stine et al, 2003;Catalano et al, 2006;Rönicke et al, 2011). The scrambled A␤ 1-42 (catalog #25382; AnaSpec) was labeled by incubating the peptide with TMR (6-carboxytetramethylrhodamine, succinimidyl-ester; Invitrogen) in HEPES buffer, pH 7.4, for 24 h in 4°C at a 1:2 ratio.…”

Section: Methodsmentioning

confidence: 99%

“…This preparation method is well known to result in oligomers, not fibrils (Stine et al, 2003;Catalano et al, 2006;Rönicke et al, 2011). Transmission electron microscopy (TEM) images of the oA␤ preparations directly after incubation (0 h), that is the time point the oA␤ 1-42 were otherwise added to the cells, identified them (90 -95%) as being primarily heterogeneous assemblies of oligomers, with diameters ranging from 1 to 10 nm; 5-10% of the oligomers had diameters Ͼ 10 nm (Fig.…”

Section: Possible Mechanism Of Transmissionmentioning

confidence: 99%

Spreading of Neurodegenerative Pathology via Neuron-to-Neuron Transmission of -Amyloid

Nath¹,

Agholme²,

Kurudenkandy³

et al. 2012

Journal of Neuroscience

218

222

View full text Add to dashboard Cite

Alzheimer's disease (AD) is the major cause of dementia. During the development of AD, neurofibrillary tangles progress in a fixed pattern, starting in the transentorhinal cortex followed by the hippocampus and cortical areas. In contrast, the deposition of ␤-amyloid (A␤) plaques, which are the other histological hallmark of AD, does not follow the same strict spatiotemporal pattern, and it correlates poorly with cognitive decline. Instead, soluble A␤ oligomers have received increasing attention as probable inducers of pathogenesis. In this study, we use microinjections into electrophysiologically defined primary hippocampal rat neurons to demonstrate the direct neuron-to-neuron transfer of soluble oligomeric A␤. Additional studies conducted in a human donor-acceptor cell model show that this A␤ transfer depends on direct cellular connections. As the transferred oligomers accumulate, acceptor cells gradually show beading of tubulin, a sign of neurite damage, and gradual endosomal leakage, a sign of cytotoxicity. These observations support that intracellular A␤ oligomers play a role in neurodegeneration, and they explain the manner in which A␤ can drive disease progression, even if the extracellular plaque load is poorly correlated with the degree of cognitive decline. Understanding this phenomenon sheds light on the pathophysiological mechanism of AD progression. Additional elucidation will help uncover the detailed mechanisms responsible for the manner in which AD progresses via anatomical connections and will facilitate the development of new strategies for stopping the progression of this incapacitating disease.

show abstract

“…Although the mechanism of neurodegeneration in Alzheimer's disease is still unclear, the leading theory implicates the accumulation and aggregation of amyloid-β peptides into a variety of soluble oligomers, ranging in size from 4 to 20 monomers, instead of the insoluble fibrils found in plaque (Billings et al, 2005;Catalano et al, 2006;Chromy et al, 2003;Kayed et al, 2003;Klein et al, 2004;Lesne et al, 2006;Petkova et al, 2005;Selkoe, 2004). These small toxic oligomers may then initiate a second sequence, associated with the hyperphosphorylation of tau followed by aggregation into neurofibrillary tangles, another hallmark of Alzheimer's neuropathogenesis in humans (Avila, 2006;Binder et al, 2005;Churcher, 2006;Gotz et al, 2001;Lee and Trojanowski, 2006;Oddo et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Brain and behavior changes in 12-month-old Tg2576 and nontransgenic mice exposed to anesthetics

Bianchi

Tran

Liu

et al. 2008

Neurobiology of Aging

216

187

View full text Add to dashboard Cite

Inhaled anesthetics have been shown to increase the aggregation of amyloid beta in vitro through the stabilization of intermediate toxic oligomers, which are thought to contribute to neurocognitive dysfunction in Alzheimer's disease. Inhaled anesthetics may escalate cognitive dysfunction through enhancement of these intermediate oligomer concentrations. We intermittently exposed 12-month-old Tg2576 transgenic mice and nontransgenic littermates to isoflurane and halothane for 5 days. Cognitive function was measured before and after anesthetic exposures using the Morris Water Maze; amyloid beta plaque burden and caspase-3 mediated apoptosis were quantified by immunohistochemistry. At 12 months of age, anesthetic exposure did not further enhance cognitive decline in the transgenic mice. Immunohistochemistry, however, revealed that the halothane-exposed Tg2576 mice had more amyloidopathy than the isoflurane treated mice or the nonexposed transgenic mice. Isoflurane exposure impaired cognitive function in the nontransgenic mice, implying an alternative pathway for neurodegeneration. These findings indicate that inhaled anesthetics influence cognition and amyloidogenesis, but that the mechanistic relationship remains unclear.

show abstract

The Role of Amyloid-Beta Derived Diffusible Ligands (ADDLs) in Alzheimers Disease

Cited by 102 publications

References 118 publications

Heat Shock Proteins 70 and 90 Inhibit Early Stages of Amyloid β-(1–42) Aggregation in Vitro

Heat Shock Proteins 70 and 90 Inhibit Early Stages of Amyloid β-(1–42) Aggregation in Vitro

Spreading of Neurodegenerative Pathology via Neuron-to-Neuron Transmission of -Amyloid

Brain and behavior changes in 12-month-old Tg2576 and nontransgenic mice exposed to anesthetics

Contact Info

Product

Resources

About