β-Amyloid peptides enhance α-synuclein accumulation and neuronal deficits in a transgenic mouse model linking Alzheimer's disease and Parkinson's disease
Eliezer Masliah,Edward Rockenstein,Isaac Veinbergs,Yutaka Sagara,Margaret Mallory,Makoto Hashimoto,Lennart Mucke +6 more
TLDR
Treatments that block the production or accumulation of β-amyloid peptides could benefit a broader spectrum of disorders than previously anticipated.Abstract:
Alzheimer's disease and Parkinson's disease are associated with the cerebral accumulation of beta-amyloid and alpha-synuclein, respectively. Some patients have clinical and pathological features of both diseases, raising the possibility of overlapping pathogenetic pathways. We generated transgenic (tg) mice with neuronal expression of human beta-amyloid peptides, alpha-synuclein, or both. The functional and morphological alterations in doubly tg mice resembled the Lewy-body variant of Alzheimer's disease. These mice had severe deficits in learning and memory, developed motor deficits before alpha-synuclein singly tg mice, and showed prominent age-dependent degeneration of cholinergic neurons and presynaptic terminals. They also had more alpha-synuclein-immunoreactive neuronal inclusions than alpha-synuclein singly tg mice. Ultrastructurally, some of these inclusions were fibrillar in doubly tg mice, whereas all inclusions were amorphous in alpha-synuclein singly tg mice. beta-Amyloid peptides promoted aggregation of alpha-synuclein in a cell-free system and intraneuronal accumulation of alpha-synuclein in cell culture. beta-Amyloid peptides may contribute to the development of Lewy-body diseases by promoting the aggregation of alpha-synuclein and exacerbating alpha-synuclein-dependent neuronal pathologies. Therefore, treatments that block the production or accumulation of beta-amyloid peptides could benefit a broader spectrum of disorders than previously anticipated.read more
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Neuropathological Alterations in Alzheimer Disease
TL;DR: Postmortem studies have enabled the staging of the progression of both amyloid and tangle pathologies, and the development of diagnostic criteria that are now used worldwide, and these cross-sectional neuropathological data have been largely validated by longitudinal in vivo studies using modern imaging biomarkers such as amyloids PET and volumetric MRI.
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Molecular pathways of neurodegeneration in Parkinson's disease.
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TL;DR: Strategies aimed at restoring complex I activity, reducing oxidative stress and α-synuclein aggregation, and enhancing protein degradation may hold particular promise as powerful neuroprotective agents in the treatment of PD.
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Alzheimer mechanisms and therapeutic strategies.
Yadong Huang,Lennart Mucke +1 more
TL;DR: Investigative and drug development efforts should be diversified to fully address the multifactoriality of Alzheimer's disease.
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Molecular pathophysiology of parkinson's disease
TL;DR: Increasing evidence indicates that deficits in mitochondrial function, oxidative and nitrosative stress, the accumulation of aberrant or misfolded proteins, and ubiquitin-proteasome system dysfunction may represent the principal molecular pathways or events that commonly underlie the pathogenesis of sporadic and familial forms of PD.
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Inflammation in Neurodegenerative Disease—A Double-Edged Sword
Tony Wyss-Coray,Lennart Mucke +1 more
TL;DR: Since many inflammatory responses are beneficial, directing and instructing the inflammatory machinery may be a better therapeutic objective than suppressing it.
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