Should we lower or raise levels of amyloid-β in the brains of Alzheimer patients?

Imbimbo, Bruno P.; Ippati, Stefania; Imbimbo, Camillo; Balducci, Claudia

doi:10.1016/j.phrs.2022.106390

Cited by 3 publications

(1 citation statement)

References 25 publications

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“…The absence of direct detection by imaging techniques and the difficulties of purification of intact oligomeric conformations from brain tissue contribute to a certain level of indeterminacy. This and other observations have been used to minimize the pathogenetic role of oligomers in favor of alternative mechanism theories which would require specific investigations for proof, but in any case aliment the scientific debate [13]. However, in the last two or three months several findings have converged to cast oligomers in a new light both in AD and Parkinson's disease (PD).…”

Section: Oligomers and Neurodegenerationmentioning

confidence: 99%

Oligomers and Neurodegeneration: New Evidence

Forloni

2023

Aging and disease

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In the last few months new results in Alzheimer’s (AD) and Parkinson’s disease (PD) have converged, attracting attention to oligomer species of misfolded proteins, β-amyloid (Aβ and α-synuclein (α-Syn), in the pathogenesis. The high affinity for Aβ protofibrils and oligomers of lecanemab, an antibody recently approved as a disease-modifying drug in AD, and the identification of Aβ-oligomers in blood samples as early biomarkers in subjects with cognitive decline, indicate the oligomers as a therapeutic target and diagnostic tool in AD. α-Syn oligomers were identified by new histopathological techniques in the hippocampus and visual cortex of PD subjects with a distribution distinct from the Lewy body pathologies but associated with cognitive impairment; these species purified from PD brain were highly neurotoxic. In a PD experimental model, we confirmed the presence of α-Syn oligomers associated with cognitive decline and sensitive to drug treatment.

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Section: Oligomers and Neurodegenerationmentioning

confidence: 99%

Oligomers and Neurodegeneration: New Evidence

Forloni

2023

Aging and disease

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Wwl70-induced ABHD6 inhibition attenuates memory deficits and pathological phenotypes in APPswe/PS1dE9 mice

Xue

et al. 2023

Pharmacological Research

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Investigational treatments for neurodegenerative diseases caused by inheritance of gene mutations: lessons from recent clinical trials

et al. 2023

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We reviewed recent major clinical trials with investigational drugs for the treatment of subjects with neurodegenerative diseases caused by inheritance of gene mutations or associated with genetic risk factors. Specifically, we discussed randomized clinical trials in subjects with Alzheimer’s disease, Huntington’s disease and amyotrophic lateral sclerosis bearing pathogenic gene mutations, and glucocerebrosidase-associated Parkinson’s disease. Learning potential lessons to improve future therapeutic approaches is the aim of this review. Two long-term, controlled trials on three anti-β-amyloid monoclonal antibodies (solanezumab, gantenerumab and crenezumab) in subjects carrying Alzheimer’s disease-linked mutated genes encoding for amyloid precursor protein or presenilin 1 or presenilin 2 failed to show cognitive or functional benefits. A major trial on tominersen, an antisense oligonucleotide designed to reduce the production of the huntingtin protein in subjects with Huntington’s disease, was prematurely interrupted because the drug failed to show higher efficacy than placebo and, at highest doses, led to worsened outcomes. A 28-week trial of tofersen, an antisense oligonucleotide for superoxide dismutase 1 in patients with amyotrophic lateral sclerosis with superoxide dismutase 1 gene mutations failed to show significant beneficial effects but the 1-year open label extension of this study indicated better clinical and functional outcomes in the group with early tofersen therapy. A trial of venglustat, a potent and brain-penetrant glucosylceramide synthase inhibitor, in Parkinson’s disease subjects with heterozygous glucocerebrosidase gene mutations revealed worsened clinical and cognitive performance of patients on the enzyme inhibitor compared to placebo. We concluded that clinical trials in neurodegenerative diseases with a genetic basis should test monoclonal antibodies, antisense oligonucleotides or gene editing directed against the mutated enzyme or the mutated substrate without dramatically affecting physiological wild-type variants.

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Should we lower or raise levels of amyloid-β in the brains of Alzheimer patients?

Cited by 3 publications

References 25 publications

Oligomers and Neurodegeneration: New Evidence

Oligomers and Neurodegeneration: New Evidence

Wwl70-induced ABHD6 inhibition attenuates memory deficits and pathological phenotypes in APPswe/PS1dE9 mice

Investigational treatments for neurodegenerative diseases caused by inheritance of gene mutations: lessons from recent clinical trials

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