Molecular pathogenesis of sporadic and familial forms of Alzheimer's disease

Ray, William J.; Ashall, Frank; Goate, Alison M.

doi:10.1016/s1357-4310(98)01229-5

Cited by 49 publications

(33 citation statements)

References 36 publications

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“…Patients with familial AD resulting from mutations in the APP, presenilin 1 (PS1), or presenilin 2 (PS2) genes exhibit a marked increase in Ah production and deposition into senile plaques (Hardy, 1997;Hutton and Hardy, 1997). Overproduction of Ah and its deposition into senile plaques are also frequently observed in sporadic AD cases (Ray et al, 1998;Saido, 1998). Moreover, Ah peptides exert neurotoxic effects in various systems (Loo et al, 1993;Mattson et al, 1993;Pike et al, 1995;Waite et al, 1992;Yankner et al, 1990).…”

Section: Introductionmentioning

confidence: 99%

Amyloid beta peptide directly inhibits PKC activation

Lee

Boo

Jung

et al. 2004

Molecular and Cellular Neuroscience

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Section: Introductionmentioning

confidence: 99%

Amyloid beta peptide directly inhibits PKC activation

Lee

Boo

Jung

et al. 2004

Molecular and Cellular Neuroscience

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“…It is widely considered that genetic factors, acting independently or in concert with other genetic and/or environmental factors, modify the risk of developing the disease. 3 Many genes associated with the disease have been identified. Some of these genes are involved in early onset forms of the disease and have a direct causal effect: The amyloid precursor protein (APP) gene located on chromosome 21 and presenilin genes 1 and 2 located on chromosome 14 and 1 respectively.…”

Section: Introductionmentioning

confidence: 99%

Is mitochondrial DNA depletion involved in Alzheimer's disease?

2001

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Several studies have suggested that mitochondrial metabolism disturbances and mitochondrial DNA (mtDNA) abnormalities may contribute to the progression of the pathology of Alzheimer's disease (AD). In this study we have investigated whether the amount of mtDNA is modified in different brain regions (cerebellum, hippocampus and frontal cortex) of confirmed AD necropsies and in blood of living AD patients. We used a real-time PCR method to analyse the mtDNA relative abundance in brain regions from 12 AD and seven controls and from a group of blood samples (17 living AD patients and 11 controls). MtDNA from blood samples together with hippocampus and cerebellum brain areas did not show differences between controls and AD. However, AD patients showed a 28% decrease in the amount of mtDNA in the frontal cortex when compared to controls for this specific area. Since frontal cortex is a severely affected region in AD, our results support the hypothesis that mitochondrial defects may play a role in the pathogenesis of AD. European Journal of Human Genetics (2001) 9, 279 ± 285.

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“…Other hallmarks of AD include the formation of neurofibrillary tangles in neurons, loss of synapses, and decreases in cell density in the distinct regions of the brain. These histopathological changes are observed in familial AD, which is caused by mutations in the APP or presenilin genes, in sporadic AD, and in individuals with Down's syndrome, who carry an extra copy of chromosome 21 and overexpress wild-type APP several fold in the brain (3)(4)(5)(6).…”

mentioning

confidence: 99%

β-Amyloid precursor protein transgenic mice that harbor diffuse Aβ deposits but do not form plaques show increased ischemic vulnerability: Role of inflammation

Koistinaho

Kettunen

Goldsteins

et al. 2002

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

151

114

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␤-amyloid (A␤), derived form the ␤-amyloid precursor protein (APP), is important for the pathogenesis of Alzheimer's disease (AD), which is characterized by progressive decline of cognitive functions, formation of A␤ plaques and neurofibrillary tangles, and loss of neurons. However, introducing a human wild-type or mutant APP gene to rodent models of AD does not result in clear neurodegeneration, suggesting that contributory factors lowering the threshold of neuronal death may be present in AD. Because brain ischemia has recently been recognized to contribute to the pathogenesis of AD, we studied the effect of focal brain ischemia in 8-and 20-month-old mice overexpressing the 751-amino acid isoform of human APP. We found that APP751 mice have higher activity of p38 mitogen-activated protein kinase (p38 MAPK) in microglia, the main immune effector cells within the brain, and increased vulnerability to brain ischemia when compared with age-matched wild-type mice. These characteristics are associated with enhanced microglial activation and inflammation but not with altered regulation of cerebral blood flow, as assessed by MRI and laser Doppler flowmetry. Suppression of inflammation with aspirin or inhibition of p38 MAPK with a selective inhibitor, SD-282, abolishes the increased neuronal vulnerability in APP751 transgenic mice. SD-282 also suppresses the expression of inducible nitric-oxide synthase and the binding activity of activator protein 1. These findings elucidate molecular mechanisms of neuronal injury in AD and suggest that antiinflammatory compounds preventing activation of p38 MAPK in microglia may reduce neuronal vulnerability in AD.T he ␤-amyloid precursor protein (APP) is a ubiquitous transmembrane glycoprotein and the source of ␤-amyloid peptides (A␤), which are the principal components of amyloid plaques in the brain of patients with Alzheimer's disease (AD), an age-related neurodegenerative disease associated with progressive decline of cognitive functions (1, 2). Other hallmarks of AD include the formation of neurofibrillary tangles in neurons, loss of synapses, and decreases in cell density in the distinct regions of the brain. These histopathological changes are observed in familial AD, which is caused by mutations in the APP or presenilin genes, in sporadic AD, and in individuals with Down's syndrome, who carry an extra copy of chromosome 21 and overexpress wild-type APP several fold in the brain (3-6).Substantial evidence indicates importance of APP for the pathogenesis of AD, but the mechanism how APP increases neuronal vulnerability in AD is unclear. A large number of epidemiological studies indicate that inflammatory events are involved because antiinflammatory drugs slow the progression of the disease, and reactive microglia and proinflammatory molecules that are secreted by microglia are present at sites of amyloid plaques (7-11). The inflammation hypothesis is further supported by the findings that secreted derivatives of APP (sAPP-␣) and A␤ activate microglial cells resulting in death ...

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Molecular pathogenesis of sporadic and familial forms of Alzheimer's disease

Cited by 49 publications

References 36 publications

Amyloid beta peptide directly inhibits PKC activation

Amyloid beta peptide directly inhibits PKC activation

Is mitochondrial DNA depletion involved in Alzheimer's disease?

β-Amyloid precursor protein transgenic mice that harbor diffuse Aβ deposits but do not form plaques show increased ischemic vulnerability: Role of inflammation

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