COMMENT The approach is interesting and may provide insights into synaptosome characteristics that reflect synaptic function. Many mRNAs translated in the synaptic spine, such as neurotransmitter receptors, are important for post-synaptic function and regulation.
Robert Vassar on An isogenic panel of App knock-in mouse models: Profiling β-secretase inhibition and endosomal abnormalities.
COMMENT This is a useful model to add to the armamentarium of mice to investigate amyloid pathology. It will be particularly useful for testing dose-response relationships of BACE1 inhibitors in vivo. The Swedish mutation makes APP such a strong substrate for BAC
COMMENT This is an interesting technology with the potential for deep interrogation of protein content in synapses and how they change with age or disease. It would be interesting to see if the technology could be adapted to interrogate other parts of the neuron,
COMMENT This new, interesting mutation offers yet additional compelling evidence in favor of the amyloid cascade hypothesis. Interestingly, the Uppsala APP mutation seems to cause AD by both increasing BACE1 cleavage of APP to generate more Aβ, but it also alters
COMMENT Bart De Strooper's thoughtful and cogent comments provide compelling guidance for the AD
COMMENT The approval of aducanumab, although controversial, may open new opportunities in the areas of prevention and combination trials for AD. Prevention trials administering aducanumab to asymptomatic, amyloid-positive individuals should move forward. For a co
COMMENT Stefan Lichtenthaler gave an outstanding talk at AD/PD 2021. He presented very compelling mass spectrometry data that GP130 is a robust BACE1 substrate. It will be interesting to see what role this new BACE1 substrate may have regarding the cognitive wors
COMMENT I found it very interesting that Eisai did not observe the cognitive worsening that other BACE1 inhibitors have reported. Given that the majority of the other BACE1 inhibitors exhibited the cognitive worsening side effect, I originally concluded the decli
Robert Vassar, Shahrnaz Kemal on Tau deletion reduces plaque-associated BACE1 accumulation and decelerates plaque formation in a mouse model of Alzheimer's disease.
COMMENT This is an interesting finding that reveals further clues about the interplay between Aβ, BACE1, and tau. The use of in vivo two-photon imaging in APP/PS1 mice either with or without tau is a powerful technique that allows individual plaques to be tracked
COMMENT I agree with Paul Aisen’s remarks. The evidence that Aβ is a key initiator of AD is overwhelming, and BACE inhibition early in the disease process should therefore prevent AD. However, BACE has many substrates that perform important functions in the brain
COMMENT We are at a critical juncture for BACE1 inhibition research. The disappointing results of the recent BACE1 inhibitor clinical trials is giving way to the sentiment that BACE1 is too risky a therapeutic target to pursue for AD. This feeling is understandab
COMMENT The discovery of η-secretase processing of APP is an intriguing finding that may have important implications for BACE inhibition as a therapeutic approach for AD. Willem and colleagues convincingly show that BACE inhibition increases the Aη-α fragment in
COMMENT The paper by Kovacs and colleagues reports the discovery that a significant proportion of APP in the cell is palmitoylated and enriched in lipid rafts. APP palmitoylation increased the colocalization of APP with BACE1, the β-secretase. Consequently, BACE1
Robert Vassar on Identification of neuronal RNA targets of TDP-43-containing ribonucleoprotein complexes.
COMMENT This paper by Gang Yu and colleagues describes a very interesting study to identify the set of RNAs that bind to TDP-43, a protein that has been implicated in a wide range of neurodegenerative diseases. The authors performed an unbiased screen of TDP-43 R
Robert Vassar on Hypoglycemic episodes and risk of dementia in older patients with type 2 diabetes mellitus.
COMMENT This paper fits with our hypothesis that glucose deprivation increases BACE1 mRNA translation and hence increases the risk of AD, as type 2 diabetes has been shown to do epidemiologically. However, the study has not investigated mechanism, so the jury is