Conformational targeting of intracellular Aβ oligomers demonstrates their pathological oligomerization inside the endoplasmic reticulum

Meli, Giovanni; Lecci, Agnese; Manca, A; Krako, Nina; Albertini, Valentina; Benussi, Luisa; Ghidoni, Roberta; Cattaneo, Antonino

doi:10.1038/ncomms4867

Cited by 54 publications

(71 citation statements)

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“…The finding of intracellular Aβ accumulation in AD retinas, either somatic or perinuclear, suggests an alternate mode of Aβ-mediated toxicity. Recent studies have demonstrated the detrimental effects of intracellular Aβ, by way of oligomerization into pathological forms within the endoplasmic reticulum (88), as well as the formation of neuritic plaques from degenerating neurons containing intracellular Aβ (89).…”

Section: Discussionmentioning

confidence: 99%

Retinal amyloid pathology and proof-of-concept imaging trial in Alzheimer’s disease

et al. 2017

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BACKGROUND. Noninvasive detection of Alzheimer's disease (AD) with high specificity and sensitivity can greatly facilitate identification of at-risk populations for earlier, more effective intervention. AD patients exhibit a myriad of retinal pathologies, including hallmark amyloid β-protein (Aβ) deposits. METHODS.Burden, distribution, cellular layer, and structure of retinal Aβ plaques were analyzed in flat mounts and cross sections of definite AD patients and controls (n = 37). In a proof-of-concept retinal imaging trial (n = 16), amyloid probe curcumin formulation was determined and protocol was established for retinal amyloid imaging in live patients. RESULTS.Histological examination uncovered classical and neuritic-like Aβ deposits with increased retinal Aβ 42 plaques (4.7-fold; P = 0.0063) and neuronal loss (P = 0.0023) in AD patients versus matched controls. Retinal Aβ plaque mirrored brain pathology, especially in the primary visual cortex (P = 0.0097 to P = 0.0018; Pearson's r = 0.84-0.91). Retinal deposits often associated with blood vessels and occurred in hot spot peripheral regions of the superior quadrant and innermost retinal layers. Transmission electron microscopy revealed retinal Aβ assembled into protofibrils and fibrils. Moreover, the ability to image retinal amyloid deposits with solid-lipid curcumin and a modified scanning laser ophthalmoscope was demonstrated in live patients. A fully automated calculation of the retinal amyloid index (RAI), a quantitative measure of increased curcumin fluorescence, was constructed. Analysis of RAI scores showed a 2.1-fold increase in AD patients versus controls (P = 0.0031). CONCLUSION.The geometric distribution and increased burden of retinal amyloid pathology in AD, together with the feasibility to noninvasively detect discrete retinal amyloid deposits in living patients, may lead to a practical approach for large-scale AD diagnosis and monitoring.

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Section: Discussionmentioning

confidence: 99%

Retinal amyloid pathology and proof-of-concept imaging trial in Alzheimer’s disease

et al. 2017

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Section: Glutamate Modulationmentioning

confidence: 99%

“…However, they appear largely not exploitable for subcellular targeting and intracellular functional studies in living cells. In 2014 Meli et al, generated, by an in vivo intracellular selection in yeast cells, a set of conformation-sensitive antibody fragments for different subcellular compartments [147], developing a CSI method. This approach allowed to determine the cellular mechanisms of AbO generation, demonstrating that intracellular amyloid bodies can oligomerize into pathological forms through critical conformations formed inside the endoplasmic reticulum (ER).…”

Section: Glutamate Modulationmentioning

confidence: 99%

“…This approach allowed to determine the cellular mechanisms of AbO generation, demonstrating that intracellular amyloid bodies can oligomerize into pathological forms through critical conformations formed inside the endoplasmic reticulum (ER). The anti-AbO intrabody selectively intercepts critical AbO conformers and controls their 'toxic' assembly in the ER, without interfering with the complex processes of maturation and processing of APP [147].As regards the relationship between AD and POAG, Cheung and co-workers were among the first to suggest that, since the neurodegeneration that affects patients with glaucoma refers to similar pathogenic mechanisms as AD and PD (glutamate excitotoxicity, mitochondrial dysfunction, protein misfolding, oxidative stress, inflammation and deprivation of neurotrophins), then, also from a therapeutic point of view, such neurodegeneration can be dealt with by similar therapeutic strategies [148]. In support of this concept, many publications support the use of molecules traditionally employed in the treatment of classic neurodegenerative diseases also in the treatment of glaucoma [149].…”

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Critical Review on the Relationship between Glaucoma and Alzheimer's Disease

Pescosolido¹,

Pascarella²,

Buomprisco³

et al. 2014

AOVS

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two distinct pathologies, despite similar pathophysiology and demographic distribution. Both diseases are neurodegenerative, chronic and progressive in nature, with irreversible neuronal cell loss. Furthermore, both POAG and AD disease primarily affect the elderly, with a strongly age-dependent incidence. The progressive debilitating course of both diseases has tremendous implications on an aging population [1]. For years Glaucoma has been associated with high IOP [2], although scientists had accepted this etiology with caution, since it was known that POAG could develop in subjects with normal or even low IOP. In fact, one out of three POAG patients has normotensive or low tension glaucoma [3]. This observation has led the scientific community to look for other possible causes of this slowly debilitating pathogenesis.The hallmark of neurodegenerative diseases is the death of specific neuron populations, and of those other neurons that are inter-connected and depend for their survival on the inputs from the main population (trans-synaptic degeneration). In Parkinson's disease accumulation of alfa-synuclein [4] causes the degeneration of dopaminergic neurons of the substantia nigra, in the midbrain, thus leading to the classic symptoms of Parkinson's such as tremor, akinesia, bradykinesia, and stiffness [5]. In AD there is a loss of neurons in the cerebral cortex and certain subcortical regions. This loss results in gross atrophy of the affected regions, including degeneration in the temporal lobe and parietal lobe, and parts of the frontal cortex and cingulate gyrus [6]. Both amyloid plaques and neurofibrillary tangles are AbstractA third of people affected by primary open angle glaucoma (POAG) have normal or even low intraocular pressure (IOP), such as in the case of normotensive glaucoma and low pressure glaucoma. Therefore, high IOP, while remaining the most important risk factor for POAG development, is not the only one. POAG has been recognized to belong to the class of neurodegenerative diseases, such as Alzheimer's (AD) and Parkinson's, and several recent studies have suggested possible links between Alzheimer's and glaucoma both from an epidemiological and a pathogenetic point of view. In fact, several pathogenetic factors are common between the two diseases: the diffuse axonal degeneration of ganglion cells, the presence of specific markers (such as amyloid-β) in the aqueous humor, the activation of caspases and the abnormal processing of amyloid precursor protein in retinal ganglion cells, the reduction of the intracranial pressure of the cerebrospinal fluid, the mutations of the gene that encodes for optineurine. Conflicting data have been reported concerning apolipoprotein E. Finally, numerous publications affirm the utility of molecules traditionally used in the treatment of neurodegenerative diseases (e.g. forskolin, L-carnosine, homotaurine, folic acid, acetylcholinesterase inhibitors, antioxidant vitamins, glatiramer acetate, etc.) also in the treatment of glaucoma.In the present research we ana...

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“…There is increasing evidence suggesting that oligomers, probably the most neuropathogenic Ab species for disrupting synaptic and cognitive function, play a central role in the onset and progression of AD. [21][22][23] Current data showed that immunotherapy targeting or neutralizing Ab oligomers was effective in protecting cognitive function, and the effects correlated positively with levels of antibodies. [24][25][26] Anti-Ab antibodies incapable of reducing cerebral Ab oligomers failed to attenuate spatial memory deficits in AD model mice.…”

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confidence: 99%

Prophylactic immunotherapy of Alzheimer's disease using recombinant amyloid-β B-cell epitope chimeric protein as subunit vaccine

Yu¹,

Chen

2016

Human Vaccines & Immunotherapeutics

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Alzheimer's disease (AD) is a neurodegenerative disorder that impairs memory and cognition. The neuropathological features of the disease include senile plaques (SPs), neurofibrillary tangles (NFTs) and neuronal loss in affected brain regions. The amyloid cascade hypothesis suggests that production and accumulation of excessive amyloid-b (Ab) may be the main cause in the onset and progression of Alzheimer's disease. Active and passive immunotherapy targeting Ab may be the most promising strategy to prevent or treat AD. This commentary focuses on the prophylactic immunotherapy of Alzheimer's disease using recombinant Ab B-cell epitope chimeric protein as subunit vaccine targeting amyloid-b. We discuss the efficiency and perspective of this type of recombinant subunit protein vaccine and suggest a novel direction on the path to a successful AD immunotherapy. This novel chimeric protein immunogen as subunit vaccine of AD may be designed to mimic the assembly states of Ab42 or oligomers using multivalent foldable Ab1-15 (B cell epitopes of Ab42) and foreign T helper (Th) epitopes (as the T cell epitopes of Ab42) constructs. Alzheimer's disease (AD) is the most common form of ageassociated dementia in the elderly. As a neurodegenerative disease, it is a debilitating disorder that can lead to significant cognitive deficits and ultimately lead to complete dependency and death. AD is characterized by senile plaques (SPs) and neurofibrillary tangles (NFTs). The onset and progression of AD is thought to be caused by the production and accumulation of excessive amyloid-b (Ab) in the brain, which results in amyloid plaque deposition as a defining pathological hallmark, and ultimately leads to neuron loss, cognitive decline and brain atrophy.

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Conformational targeting of intracellular Aβ oligomers demonstrates their pathological oligomerization inside the endoplasmic reticulum

Cited by 54 publications

References 70 publications

Retinal amyloid pathology and proof-of-concept imaging trial in Alzheimer’s disease

Retinal amyloid pathology and proof-of-concept imaging trial in Alzheimer’s disease

Critical Review on the Relationship between Glaucoma and Alzheimer's Disease

Prophylactic immunotherapy of Alzheimer's disease using recombinant amyloid-β B-cell epitope chimeric protein as subunit vaccine

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