Further evidence for an association between a mutation in the APP gene and Lewy body formation

Halliday, Glenda M.; Brooks, William S.; Arthur, Helen; Creasey, Helen; Broe, G. A.

doi:10.1016/s0304-3940(97)00294-2

Cited by 26 publications

(15 citation statements)

References 22 publications

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“…43–45 Occasionally, there is pathological discordance with a single gene defect; within a single family, some APP mutation carriers may develop Lewy body pathology and others may not, yet all may have AD pathology. 38,44 …”

Section: Discussionmentioning

confidence: 99%

Clinical Features of Alzheimer Disease With and Without Lewy Bodies

et al. 2015

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Section: Discussionmentioning

confidence: 99%

Clinical Features of Alzheimer Disease With and Without Lewy Bodies

et al. 2015

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“…42 Laboratory studies indicate that mismetabolism of the amyloid beta precursor protein (APP) gene may trigger Lewy body formation. [43][44][45] Occasionally, there is pathological discordance with a single gene defect; within a single family, some APP mutation carriers may develop Lewy body pathology and others may not, yet all may have AD pathology. 38,44 Differences in NPI-Q total scores were only statistically significant in the model that did not adjust for APOE ε4.…”

Section: Discussionmentioning

confidence: 99%

“…[43][44][45] Occasionally, there is pathological discordance with a single gene defect; within a single family, some APP mutation carriers may develop Lewy body pathology and others may not, yet all may have AD pathology. 38,44 Differences in NPI-Q total scores were only statistically significant in the model that did not adjust for APOE ε4. Participants who had AD with at least 1 APOE ε4 allele have a greater risk than noncarriers for developing neuropsychiatric symptoms, especially delusions and hallucinations.…”

Section: Discussionmentioning

confidence: 99%

P1‐206: Clinical features of Alzheimer disease with and without lewy bodies

Chung

Babulal

Monsell

et al. 2015

Alzheimer's & Dementia

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edu).Role of the Funder/Sponsor: The funders/sponsors had no role in the design and conduct of the study; collection, management, analysis, or interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.Supplemental content at jamaneurology.com Author Contributions: Dr Morris had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Conflict of Interest Disclosures:Dr Morris has participated or is currently participating in clinical trials of antidementia drugs sponsored by the following companies and studies: Janssen Immunotherapy, Pfizer, Eli Lilly/Avid Radiopharmaceuticals, the SNIFF (Study of Nasal Insulin to Fight Forgetfulness) study, and the A4 (Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease) trial. Dr Morris has served as a consultant for Lilly USA, ISIS Pharmaceuticals, and the Charles Dana Foundation. He receives research support from Eli Lilly/Avid Radiopharmaceuticals and is funded by National Institutes of Health grants P50AG005681, P01AG003991, P01AG026276, and U19AG032438.Additional Information: The NACC database is funded by NIA/National Institutes of Health grant U01 AG016976. The NACC data were obtained from the NIA-funded AD centers (grants P30 AG019610 [PI Eric Reiman, MD] EXPOSURES-Standardized neuropathologic assessment and then brain autopsy after death. HHS Public Access MAIN OUTCOMES AND MEASURES-Clinical and neuropsychiatric test scores.RESULTS-The mean (SD) age at death was statistically significantly younger for participants who had AD with Lewy bodies (77.9 [9.5] years) than for participants who had AD without Lewy bodies (80.2 [11.1] years) (P = .01). The mean (SD) age at onset of dementia symptoms was also younger for participants who had AD with Lewy bodies (70.0 [9.9] years) than for participants who had AD without Lewy bodies (72.2 [12.3] years) (P = .03). More men than women had AD with Lewy bodies (P = .01). The frequency of having at least 1 APOE ε4 allele was higher for participants who had AD with Lewy bodies than for participants who had AD without Lewy bodies (P = .03). CONCLUSIONS AND RELEVANCE-Participants with both AD and Lewy body pathology have a clinical phenotype that may be distinguished from AD alone. The frequency of Lewy bodies in AD and the association of Lewy bodies with the APOE ε4 allele suggest potential common mechanisms for AD and Lewy body pathologies.The 2 neuropathological hallmarks of Alzheimer disease (AD) are the extracellular Aβ plaques and the intracellular neurofibrillary tangles, of which the latter is composed of hyperphosphorylated tau protein. 1 Lewy bodies are intraneuronal cytoplasmic inclusions comprising aggregates of α-synuclein 2,3 and are readily detected by immunohistochemistry using anti-α-synuclein antibodies. In up to 50% of cases of sporadic late-onset AD, comorbid Lewy bodies are found. 2 Lewy bodies are frequent in the setting of moderate-tosevere levels of A...

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“…(e-j) Neuronal GT1-7 cells stably transfected with SYN cDNA (e-g) or control plasmid (h-j) as described (27), were left untreated (e and h) or exposed for 48 h to A␤1-40 ( f and i), A␤1-42 (g and j), or A␤42-1 (not shown) at 2 M final concentration, followed by immunoperoxidase staining with anti-SYN (27). (47)(48)(49). Our study demonstrates that hSYN and hAPP͞A␤ have distinct, as well as convergent, pathogenic effects on the integrity and function of the brain.…”

Section: A␤ Promotes Accumulation Of Hsynmentioning

confidence: 99%

β-Amyloid peptides enhance α-synuclein accumulation and neuronal deficits in a transgenic mouse model linking Alzheimer's disease and Parkinson's disease

Masliah

Rockenstein

Veinbergs

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

567

466

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Alzheimer's disease and Parkinson's disease are associated with the cerebral accumulation of ␤-amyloid and ␣-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 ␤-amyloid peptides, ␣-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 ␣-synuclein singly tg mice, and showed prominent agedependent degeneration of cholinergic neurons and presynaptic terminals. They also had more ␣-synuclein-immunoreactive neuronal inclusions than ␣-synuclein singly tg mice. Ultrastructurally, some of these inclusions were fibrillar in doubly tg mice, whereas all inclusions were amorphous in ␣-synuclein singly tg mice. ␤-Amyloid peptides promoted aggregation of ␣-synuclein in a cell-free system and intraneuronal accumulation of ␣-synuclein in cell culture. ␤-Amyloid peptides may contribute to the development of Lewy-body diseases by promoting the aggregation of ␣-synuclein and exacerbating ␣-synuclein-dependent neuronal pathologies. Therefore, treatments that block the production or accumulation of ␤-amyloid peptides could benefit a broader spectrum of disorders than previously anticipated.A ging is a major risk factor for neurodegenerative disorders, such as Alzheimer's disease (AD) and Parkinson's disease (PD), and the number of people with these conditions is increasing rapidly. In the United States alone, an estimated 4 million people have AD and at least one million have PD. Within the next 40-50 years, these numbers are projected to increase to over 8 million for AD and to 4 million for PD. Each neurodegenerative disease appears to have a predilection for specific brain regions and cell populations. However, human cases with clinical and neuropathological features of both AD and PD (1-3) raise the possibility that these diseases involve overlapping pathways.Many AD patients develop signs of PD and some PD patients become demented (3). Both diseases are associated with degeneration of neurons and interneuronal synaptic connections, depletion of specific neurotransmitters, and abnormal accumulation of misfolded proteins, whose precursors participate in normal central nervous system functions (4-11). The ␤-amyloid protein precursor (APP) and ␣-synuclein (SYN) are expressed abundantly in synapses, are well conserved across species, and have been implicated in neural plasticity, learning, and memory (6,7,12). Mutations in human APP (hAPP) that increase production of hAPP-derived ␤-amyloid peptides (A␤) cause autosomal dominant forms of familial AD (FAD) (11), and expression of FAD-mutant hAPPs in neurons of transgenic (tg) mice results in the age-dependent development of AD-like central nervous system alterations (13-17). Mutations in human SYN (hSYN) that enhance hSYN aggregation have bee...

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Further evidence for an association between a mutation in the APP gene and Lewy body formation

Cited by 26 publications

References 22 publications

Clinical Features of Alzheimer Disease With and Without Lewy Bodies

Clinical Features of Alzheimer Disease With and Without Lewy Bodies

P1‐206: Clinical features of Alzheimer disease with and without lewy bodies

β-Amyloid peptides enhance α-synuclein accumulation and neuronal deficits in a transgenic mouse model linking Alzheimer's disease and Parkinson's disease

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