Rachael Neve on Presenilin Loss of Function—Plan B for AD?

COMMENT Thank you to Jie Shen and Raymond Kelleher for kicking off this discussion with their very provocative hypothesis published in PNAS. There have been many interesting comments posted—but one thing that strikes me is the (often unspoken) assumption made in ...

Rachael Neve on Gain or Loss of Function—Time to Shake up Assumptions on γ-Secretase in Alzheimer Disease?

COMMENT Three papers published within the last two weeks highlight the potential importance of presenilin and amyloid precursor protein (APP) signaling in the etiology of Alzheimer disease (AD):  Engel et al., Full reversal of Alzheimer’s disease-like phenotype ...

Rachael Neve on APP Double Dose Causes Early Onset AD

COMMENT Obviously, the excitement of the paper derives from the fact that simple duplication of the APP gene can cause AD. Scientists had always assumed that it is the extra copy of APP that is responsible for the Alzheimer disease pathology that develops in ...

Rachael Neve on The last neuronal division: a unifying hypothesis for the pathogenesis of Alzheimer's disease.

COMMENT Nagy proposes the very intriguing hypothesis that it is not cell cycle activation per se that may cause neurodegeneration in AD, but rather, it is the inability of AD neurons to return to the differentiated state after normal activation of cell cycle ...

Rachael Neve on Neurodegenerative mutants in Drosophila: a means to identify genes and mechanisms involved in human diseases?

COMMENT This is an excellent, well-written, thorough review that shows us that invertebrate models have revealed, and continue to reveal, valuable information about the mechanistic bases of human neurodegenerative diseases. neve 0 ...

Rachael Neve on Altered gene expression and neuropathology in Alzheimer's disease.

COMMENT A very thoughtful commentary that provides good insights into how transgenic animal models for AD should be evaluated. neve 0 ...

Rachael Neve on High beta-secretase activity elicits neurodegeneration in transgenic mice despite reductions in amyloid-beta levels: implications for the treatment of Alzheimer disease.

COMMENT A number of human (h) BACE1 (β-site APP cleaving enzyme) transgenic mice have been generated and described. While these papers emphasized changes in APP processing, and in one case, behavior, they did not shed light on potential neurodegenerative ...

Rachael Neve on Familial Alzheimer's disease mutations inhibit gamma-secretase-mediated liberation of beta-amyloid precursor protein carboxy-terminal fragment.

COMMENT This very interesting article presents data to support the idea that both class II FAD APP mutations and FAD PS1 mutations not only increase levels of Aβ, but also decrease the level of AICD, called CTFγ by the authors. An extremely elegant genetic ...

Rachael Neve on Generation and characterization of mutant cell lines defective in gamma-secretase processing of Notch and amyloid precursor protein.

COMMENT This is a very clever approach for identifying cell lines that are defective in gamma-secretase processing. Also, it's interesting that the screen did not reveal additional members of the gamma-secretase complex, and that both nicastrin mutants ...

Rachael Neve on Do you remember? How caregivers question their spouses who have Alzheimer's disease and the impact on communication.

COMMENT This is a fascinating study, and is potentially very useful for people who are taking care of individuals with Alzheimer disease. neve 0 ...

Rachael Neve on The cell cycle in Alzheimer disease: a unique target for neuropharmacology.

COMMENT This is an intriguing hypothesis, that cell cycle entry coincident with oxidative stress could initiate all known pathological events in Alzheimer disease. It's definitely worth thinking about and testing. neve 0 ...

Rachael Neve on A New Program for Cell Death: Necroptosis Premiering in a Neuron Near You

COMMENT Two general mechanisms of cell death have been described: programmed cell death and necrosis. Programmed cell death, or apoptosis, is a directed program that proceeds through specific signal transduction pathways common to different cell types. In ...

Rachael Neve on Cell cycle inhibition provides neuroprotection and reduces glial proliferation and scar formation after traumatic brain injury.

COMMENT Di Giovanni and colleagues provide convincing evidence that traumatic brain injury causes upregulation of cell cycle proteins in rat brains, and that prevention of cell cycle entry attenuates the neuronal cell death and glial proliferation resulting from ...

Rachael Neve on Tissue plasminogen activator mediates amyloid-induced neurotoxicity via Erk1/2 activation.

COMMENT This paper describes a detailed (and convincing) signal transduction pathway by which amyloid kills neurons. It's a real breakthrough. neve 0 ...

Rachael Neve on Loss of neuronal cell cycle control in ataxia-telangiectasia: a unified disease mechanism.

COMMENT Ataxia-telangiectasia (A-T)is a disorder that presents with a wide spectrum of phenotypes. Many of these phenotypes, such as radiosensitivity and predisposition to malignancies, can be traced back to the breakdown of cell cycle checkpoints and DNA double ...