Dementia with Lewy bodies: an update and outlook

Outeiro, Tiago F.; Koss, David J.; Erskine, Daniel; Walker, Lauren; Kurzawa‐Akanbi, Marzena; Burn, David J.; Donaghy, Paul C.; Morris, Christopher M.; Taylor, John-Paul; Thomas, Alan; Attems, Johannes; McKeith, Ian

doi:10.1186/s13024-019-0306-8

Cited by 241 publications

(212 citation statements)

References 209 publications

(232 reference statements)

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“…It is noteworthy that disruption of the AMPKα isoform expression levels in hippocampus was found in AD, but not in LBD or FTD, postmortem brain tissue (Figure 1). LBD cases are characterized by hippocampal α-synuclein without substantial levels of p-tau (50,51). All FTD patients reported here were diagnosed with progressive supranuclear palsy, and such patients typically have increased levels of tau phosphorylation in hippocampus (52).…”

Section: Discussionmentioning

confidence: 88%

Brain-specific repression of AMPKα1 alleviates pathophysiology in Alzheimer’s model mice

Zimmermann¹,

Yang²,

Kasica³

et al. 2020

Journal of Clinical Investigation

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Figure 1. Expression of AMPKα isoforms is dysregulated in AD hippocampus. (A) Hippocampus (Hip) lysate from sAD patients showed increased AMPKα1 and decreased AMPKα2 levels as compared with those of age-matched controls (CT). n = 10 with up to 4 technical replicates. *P = 0.0119; **P = 0.0014, unpaired t test. (B) Representative images of AMPKα isoform dysregulation in area CA1 of hippocampus in AD and age-matched control patients. Scale bar: 50 μm. Immunohistochemical experiments were replicated independently 3 times. (C) AMPKα isoform expression was unaffected in cerebellum (CER) samples from AD patients. n = 5 with up to 3 technical replicates. P = 0.8457 for AMPKα1; P = 0.9870 for AMPKα2, unpaired t test. (D) Hippocampal lysate from LBD patients had unaffected AMPKα isoform levels. n = 4 for control; n = 3 for LBD with 1 technical replicate. P = 0.9146 for AMPKα1; P = 0.5635 for AMPKα2, unpaired t test. (E) Levels of AMPK isoforms were unaltered in hippocampal tissue from FTD patients. n = 8 for control with 1 technical replicate; n = 5 for FTD with up to 3 technical replicates. P = 0.9283 for AMPKα1; P = 0.335 for AMPKα2, unpaired t test. (F) AMPKα1 levels were significantly increased in cortical lysates from FAD patients, while AMPKα2 levels were unaffected. n = 5 with 4 technical replicates. **P = 0.0060 for AMPKα1; P = 0.9412 for AMPKα2, unpaired t test. (G) AMPKα1 levels were significantly increased in hippocampal lysates from Tg19959 AD model mice compared with WT controls. AMPKα2 levels were unaffected. n = 7 with up to 2 technical replicates. **P = 0.0023 for AMPKα1; P = 0.9094 for AMPKα2, unpaired t test. Box-and-whisker plots represent the interquartile range, with the line across the box indicating the median. Whiskers show the highest and lowest values detected. (H) Immunofluorescent labeling of DAPI (blue) and AMPKα1 (red) distribution in area CA1 mouse hippocampal slices. n = 3. Scale bar: 200 μm.

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Section: Discussionmentioning

confidence: 88%

Brain-specific repression of AMPKα1 alleviates pathophysiology in Alzheimer’s model mice

Zimmermann¹,

Yang²,

Kasica³

et al. 2020

Journal of Clinical Investigation

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“…Because ASyn oligomers are likely the most pathogenic misfolded ASyn species [5,46], we hypothesize that the novel non-canonical Hsp70 site responsible for blocking ASyn oligomerization also provides protection against ASyn pathogenicity in animal models and in disease (Fig 7). Further biochemical and structural mechanistic studies will be needed to determine the exact molecular mechanisms of Hsp70 suppression of ASyn oligomerization.…”

Section: Discussionmentioning

confidence: 99%

Hsp70 chaperone blocks α-synuclein oligomer formation via a novel engagement mechanism

Tao

Berthet

Citron

et al. 2020

Preprint

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Over-expression and aggregation of α-synuclein (ASyn) are linked to the onset and pathology of Parkinson's disease and related synucleinopathies. Elevated levels of the stress induced chaperone, Hsp70, protects against ASyn misfolding and ASyn-driven neurodegeneration in cell and animal models, yet there is minimal mechanistic understanding of this important protective pathway. It is generally assumed that Hsp70 binds to ASyn using its canonical and promiscuous substrate-binding cleft to limit aggregation. Here we report that this activity is due to a novel and unexpected mode of Hsp70 action, involving neither ATP nor the typical substrate-binding cleft. We use novel ASyn oligomerization assays to show that Hsp70 directly blocks ASyn oligomerization, an early event in ASyn misfolding. Using truncations, mutations and inhibitors, we confirmed that Hsp70 interacts with ASyn via an as yet unidentified, non-canonical interaction site in the C-terminal domain. Finally, a biological role for a non-canonical interaction was observed in H4 neuroglioma cells. Together, these findings suggest that new chemical approaches will be required to target Hsp70-ASyn interaction in synucleinopathies. Such approaches are likely to be more specific than targeting Hsp70 canonical actions. Additionally, these results raise the question of whether other misfolded proteins might also engage via the same non-canonical mechanism.KEYWORDS: α-Synuclein, chaperone, Hsp70, protein misfolding, Parkinson's Disease, Lewy body dementia, synucleinopathy Neuropathological, biochemical and genetic evidence strongly implicates α-Synuclein (ASyn) in the onset and progression of Parkinson's disease (PD) and related syncucleinopathies including Lewy body dementias (LBD), multiple systems atrophy and Alzheimer's disease. Aggregated ASyn inclusions are a hallmark of these diseases [1], and ASyn gene mutations or multiplications cause early onset PD or LBD [2,3,4]. The sequential misfolding of ASyn into oligomers and fibrils is central to the pathogenesis of the synucleinopathies. ASyn gene multiplications and mutations causing PD and LBD are associated with enhanced oligomer formation [5,6,7]. Significant evidence supports the hypothesis that prion-like transmission of misfolded ASyn underlies disease progression [8,9]. The severity of disease correlates with the progressive spread of aggregated ASyn in patients [10], and misfolding is associated with toxicity in cell and animal models [11]. As shown for other amyloid misfolding proteins, compelling evidence supports pre-fibrillar ASyn oligomers and not fibrillar deposits as the pathogenic species in disease [5,12,13,14,15,16]. ASyn oligomers are directly toxic to cells [16], and mutations enhancing ASyn oligomer formation increase ASyn toxicity in neurons and rodents [12,13,14].The constitutive (Hsc70) and inducible (Hsp70) forms of the 70-KDa cytosolic heat shock molecular chaperones (Hsp70s) assist a wide variety of folding processes and provide broad protection against protein misfolding in the cell. ...

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“…Amidst PD, PDD, and AD sits a disorder known as Dementia with Lewy bodies (DLB) (for review, see [Outeiro et al, 2019;Walker et al, 2015]). Clinically, DLB dementia is often distinguished from AD via the presence of unique characteristics including audio and/or visual hallucinations and DLB patients may or may not present with motor symptoms (McKeith et al, 2017) Pathologically, DLB is characterized by the presence of Lewy bodies, similar to PD, although patients may also exhibit amyloid pathology similar to AD (McKeith et al, Walker et al, 2015).…”

Section: Clinical and Pathological Characteristics Of Neurodegeneratimentioning

confidence: 99%

“…Clinically, DLB dementia is often distinguished from AD via the presence of unique characteristics including audio and/or visual hallucinations and DLB patients may or may not present with motor symptoms (McKeith et al, 2017) Pathologically, DLB is characterized by the presence of Lewy bodies, similar to PD, although patients may also exhibit amyloid pathology similar to AD (McKeith et al, Walker et al, 2015). Similar to AD and PD, DLB patients exhibit significant synaptic and neuronal loss, but research indicates that the Lewy bodies themselves are not the first neurotoxic mechanism to arise during either DLB or PD, as neuronal loss is observed prior to Lewy pathology (Milber et al, 2012;Outeiro et al, 2019). The clinical and pathological heterogeneity of DLB suggests that DLB may represent a spectrum of disorders, potentially with differing etiology and/or underlying mechanisms, which complicates the study of many disease mechanisms including the role of immune signaling.…”

Section: Clinical and Pathological Characteristics Of Neurodegeneratimentioning

confidence: 99%

Immune Signaling in Neurodegeneration

2019

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Neurodegenerative diseases of the central nervous system progressively rob patients of their memory, motor function, and ability to perform daily tasks. Advances in genetics and animal models are beginning to unearth an unexpected role of the immune system in disease onset and pathogenesis; however, the role of cytokines, growth factors, and other immune signaling pathways in disease pathogenesis is still being examined. Here we review recent genetic risk and genome-wide association studies and emerging mechanisms for three key immune pathways implicated in disease, the growth factor TGF-b, the complement cascade, and the extracellular receptor TREM2. These immune signaling pathways are important under both healthy and neurodegenerative conditions, and recent work has highlighted new functional aspects of their signaling. Finally, we assess future directions for immune-related research in neurodegeneration and potential avenues for immune-related therapies.

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Dementia with Lewy bodies: an update and outlook

Cited by 241 publications

References 209 publications

Brain-specific repression of AMPKα1 alleviates pathophysiology in Alzheimer’s model mice

Brain-specific repression of AMPKα1 alleviates pathophysiology in Alzheimer’s model mice

Hsp70 chaperone blocks α-synuclein oligomer formation via a novel engagement mechanism

Immune Signaling in Neurodegeneration

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