Lawrence Rajendran on Infrared Microscopy Reveals Pre-Plaque Formation of β-Sheets by Aβ

COMMENT By elegantly combining biophysics and in vivo structural biology, the authors identify the possible existence of tetrameric Aβ and the conformational change before plaque deposition occurs. This could suggest that, like transthyretin and the infamous α ...

Lawrence Rajendran on Partners in Crime: APP Fragment and Endosomal Protein Impair Endocytosis

COMMENT The paper is an elegant piece of work demonstrating, for the first time, the molecular basis of how b-CTF could play a role in the activation of Rab5, a process that is intricately associated with the enlargement of endosomes. Apart from the plaques and ...

Lawrence Rajendran on Pharmacological chaperones stabilize retromer to limit APP processing.

COMMENT This is a very carefully done study that combines elegant structural biology, drug discovery, cell biology, and neuroscience. Clearly, endosomal APP is an attractive target and the authors of the study have identified a pharmacological chaperone that ...

Lawrence Rajendran on New Look into Early AD Reveals Lateral Entorhinal Cortex Vulnerability

COMMENT This is a fantastic study from the Small and Duff labs, looking at the molecular origins of AD and the spread of pathology. It has great potential for identifying new biomarkers and therapeutic strategies to contain the pathology at a confined space, if ...

Lawrence Rajendran on Phosphatidylinositol-3-phosphate regulates sorting and processing of amyloid precursor protein through the endosomal system.

COMMENT This is a spectacular study, linking lipid metabolism, membrane trafficking and Alzheimer's disease. It is carefully done, combining elegant cell biology in neurons with biochemistry. For me, the most important aspect of the study is that the ...

Lawrence Rajendran on Latrepirdine improves cognition and arrests progression of neuropathology in an Alzheimer's mouse model.

COMMENT With the twin papers (one on AD and the other on α-synucleinopathy) in Mol. Psychiatry, Sam Gandy's lab revive the importance of Dimebon in amyloid disorders. Both these papers suggest a role of Dimebon in inducing autophagy and thereby ameliorating ...

Lawrence Rajendran on A multimodal RAGE-specific inhibitor reduces amyloid β-mediated brain disorder in a mouse model of Alzheimer disease.

COMMENT Alzheimer’s disease is a multifactorial and multigenetic disease. However, to procure a systems perspective on AD, it is not only important to curate a parts list of components involved in various aspects of the disease, but also to understand how they ...

Lawrence Rajendran on ADP ribosylation factor 6 (ARF6) controls amyloid precursor protein (APP) processing by mediating the endosomal sorting of BACE1.

COMMENT This elegant cell biology study adds another important piece to the puzzle of how endocytosis controls amyloid production. A few years ago, we showed that APP and BACE are internalized into early endosomes where β cleavage occurs (Rajendran et al., 2006). ...

Lawrence Rajendran on Aβ(1-42) inhibition of LTP is mediated by a signaling pathway involving caspase-3, Akt1 and GSK-3β.

COMMENT We recently witnessed the discovery of many Aβ receptors, but the exact signaling pathway through which Aβ (oligomers) mediated synaptic dysfunction (inhibition of LTP) is still not identified. This paper elegantly demonstrates the involvement of a ...

Lawrence Rajendran on Cell-produced alpha-synuclein is secreted in a calcium-dependent manner by exosomes and impacts neuronal survival.

COMMENT Cytosolic Amyloids: Being Out Is In In the last few months, the neurodegeneration community has witnessed a paradigm shift in the way we understand the spread of amyloids in the brain. Several reports suggested a prion-like behavior of amyloid proteins ...

Lawrence Rajendran on Analysis of the gamma-secretase interactome and validation of its association with tetraspanin-enriched microdomains.

COMMENT Another beautiful work on the biochemistry of γ-secretase complex from the group of Bart de Strooper. This connection to tetraspanins offers key insights into the "raft" association of γ-secretase. The raft link to APP processing is very weak ...

Lawrence Rajendran on Inclusion formation and neuronal cell death through neuron-to-neuron transmission of alpha-synuclein.

COMMENT It was a pleasure to read this work from the Masliah/Lee duo on the cell-to-cell transmission of α-synuclein (Desplats et al., 2009). This work shows that α-synuclein can be released from cells and is taken up by the neighboring cell, thereby aiding in a ...

Lawrence Rajendran on BACE Inhibitors Hitch Ride into Endosomes via Membrane Anchor

COMMENT I have to thank Alzforum's new reporter, Esther Landhuis, for the coverage on our recent study. Great work! The comment by Drs. Tang and Augelli-Szafran on the non-drug-likeness of our inhibitor is extremely important. Membrane anchoring of an ...

Lawrence Rajendran on Loss of microRNA cluster miR-29a/b-1 in sporadic Alzheimer's disease correlates with increased BACE1/beta-secretase expression.

COMMENT An excellent piece of work by Sebastien, Bart, and colleagues. This study underscores the role of BACE elevation in late-onset AD (LOAD). This study from Bart's group and the recent work from Karen Duff's group on Cdk5's role in BACE ...

Lawrence Rajendran on An alternative interpretation of the amyloid Abeta hypothesis with regard to the pathogenesis of Alzheimer's disease.

COMMENT The hypothesis by Vincent Marchesi is attractive and timely. Given that considerable effort in investigating the pathogenesis of AD is spent on the effects of plaque-associated extracellular Aβ, the article makes one rethink the direction of current ...