Hippocampal α-Synuclein in Dementia with Lewy Bodies Contributes to Memory Impairment and Is Consistent with Spread of Pathology

Adamowicz, David H.; Roy, Subhojit; Salmon, David P.; Galasko, Douglas; Hansen, Lawrence A.; Masliah, Eliezer; Gage, Fred H.

doi:10.1523/jneurosci.3047-16.2016

Cited by 94 publications

(80 citation statements)

References 65 publications

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“…Of all cornu Ammonis hippocampal fields, the small CA2 subregion displays the earliest and densest Lewy pathology in both PD and DLB . According to our previous work and the present study, the earliest and densest hippocampal pathology in fibril‐infused mice was not in CA2, but centered in ventral CA1 and the subiculum, consistent with the dense retrograde labeling of these two structures following FluoroGold infusions in the OB/AON complex and with a large body of work on the afferents of anterior olfactory brain regions (eg, see Table 2 in ) .…”

Section: Discussionsupporting

confidence: 89%

The center of olfactory bulb‐seeded α‐synucleinopathy is the limbic system and the ensuing pathology is higher in male than in female mice

et al. 2019

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At early disease stages, Lewy body disorders are characterized by limbic vs. brainstem α‐synucleinopathy, but most preclinical studies have focused solely on the nigrostriatal pathway. Furthermore, male gender and advanced age are two major risk factors for this family of conditions, but their influence on the topographical extents of α‐synucleinopathy and the degree of cell loss are uncertain. To fill these gaps, we infused α‐synuclein fibrils in the olfactory bulb/anterior olfactory nucleus complex—one of the earliest and most frequently affected brain regions in Lewy body disorders—in 3‐month‐old female and male mice and in 11‐month‐old male mice. After 6 months, we observed that α‐synucleinopathy did not expand significantly beyond the limbic connectome in the 9‐month‐old male and female mice or in the 17‐month‐old male mice. However, the 9‐month‐old male mice had developed greater α‐synucleinopathy, smell impairment and cell loss than age‐matched females. By 10.5 months post‐infusion, fibril treatment hastened mortality in the 21.5‐month‐old males, but the inclusions remained centered in the limbic system in the survivors. Although fibril infusions reduced the number of cells expressing tyrosine hydroxylase in the substantia nigra of young males at 6 months post‐infusion, this was not attributable to true cell death. Furthermore, mesencephalic α‐synucleinopathy, if present, was centered in mesolimbic circuits (ventral tegmental area/accumbens) rather than within strict boundaries of the nigral pars compacta, which were defined here by tyrosine hydroxylase immunolabel. Nonprimate models cannot be expected to faithfully recapitulate human Lewy body disorders, but our murine model seems reasonably suited to (i) capture some aspects of Stage IIb of Lewy body disorders, which displays a heavier limbic than brainstem component compared to incipient Parkinson’s disease; and (ii) leverage sex differences and the acceleration of mortality following induction of olfactory α‐synucleinopathy.

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Section: Discussionsupporting

confidence: 89%

The center of olfactory bulb‐seeded α‐synucleinopathy is the limbic system and the ensuing pathology is higher in male than in female mice

et al. 2019

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“…The majority of studies have found that PDD is associated with either limbic (transitional) or neocortical (diffuse) stage LB pathology with higher cortical LP density being observed than in nondemented PD . Neocortical LP is also associated with the onset of visual hallucinations, and hippocampal SYN pathology is associated with memory deficits even after controlling for age and co‐occurring pathologies . The current neuropathological assessment of DLB recognizes that cases with pure synucleinopathy without AD copathology are the most likely to exhibit core DLB features or visual hallucinations and fluctuations .…”

Section: The Role Of Alpha‐synuclein In Lbd Pathogenesismentioning

confidence: 99%

Pathological Influences on Clinical Heterogeneity in Lewy Body Diseases

2019

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PD, PD with dementia, and dementia with Lewy bodies are clinical syndromes characterized by the neuropathological accumulation of alpha‐synuclein in the CNS that represent a clinicopathological spectrum known as Lewy body disorders. These clinical entities have marked heterogeneity of motor and nonmotor symptoms with highly variable disease progression. The biological basis for this clinical heterogeneity remains poorly understood. Previous attempts to subtype patients within the spectrum of Lewy body disorders have centered on clinical features, but converging evidence from studies of neuropathology and ante mortem biomarkers, including CSF, neuroimaging, and genetic studies, suggest that Alzheimer's disease beta‐amyloid and tau copathology strongly influence clinical heterogeneity and prognosis in Lewy body disorders. Here, we review previous clinical biomarker and autopsy studies of Lewy body disorders and propose that Alzheimer's disease copathology is one of several likely pathological contributors to clinical heterogeneity of Lewy body disorders, and that such pathology can be assessed in vivo. Future work integrating harmonized assessments and genetics in PD, PD with dementia, and dementia with Lewy bodies patients followed to autopsy will be critical to further refine the classification of Lewy body disorders into biologically distinct endophenotypes. This approach will help facilitate clinical trial design for both symptomatic and disease‐modifying therapies to target more homogenous subsets of Lewy body disorders patients with similar prognosis and underlying biology. © 2019 International Parkinson and Movement Disorder Society

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“…PD. PD and dementia with Lewy bodies (DLB) frequently overlap with AD (Adamowicz et al, 2017;Hansen et al, 1993;Tsuboi and Dickson, 2005). For instance, in hippocampi of PD (DLB) patients, intracellular a-synuclein pathology frequently coincides with Ab and tau pathologies.…”

Section: Insulin Resistancementioning

confidence: 99%

The vicious circle of hypometabolism in neurodegenerative diseases: Ways and mechanisms of metabolic correction

Zilberter

2017

J of Neuroscience Research

183

139

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Hypometabolism, characterized by decreased brain glucose consumption, is a common feature of many neurodegenerative diseases. Initial hypometabolic brain state, created by characteristic risk factors, may predispose the brain to acquired epilepsy and sporadic Alzheimer's and Parkinson's diseases, which are the focus of this review. Analysis of available data suggests that deficient glucose metabolism is likely a primary initiating factor for these diseases, and that resulting neuronal dysfunction further promotes the metabolic imbalance, establishing an effective positive feedback loop and a downward spiral of disease progression. Therefore, metabolic correction leading to the normalization of abnormalities in glucose metabolism may be an efficient tool to treat the neurological disorders by counteracting their primary pathological mechanisms. Published and preliminary experimental results on this approach for treating Alzheimer's disease and epilepsy models support the efficacy of metabolic correction, confirming the highly promising nature of the strategy. V C 2017 Wiley Periodicals, Inc.

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Hippocampal α-Synuclein in Dementia with Lewy Bodies Contributes to Memory Impairment and Is Consistent with Spread of Pathology

Cited by 94 publications

References 65 publications

The center of olfactory bulb‐seeded α‐synucleinopathy is the limbic system and the ensuing pathology is higher in male than in female mice

The center of olfactory bulb‐seeded α‐synucleinopathy is the limbic system and the ensuing pathology is higher in male than in female mice

Pathological Influences on Clinical Heterogeneity in Lewy Body Diseases

The vicious circle of hypometabolism in neurodegenerative diseases: Ways and mechanisms of metabolic correction

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