Michael Lardelli on The National Institute on Aging and Alzheimer's Association research framework: A commentary from the Cochrane Dementia and Cognitive Improvement Group.

COMMENT This commentary is a clear and important critique of the attempt to redefine Alzheimer's disease in the "NIA-AA Research Framework." As a senior colleague stated when I showed it to him: "It is rare that anything is achieved by the ...

Michael Lardelli on Altered γ-Secretase Processing of APP Disrupts Lysosome and Autophagosome Function in Monogenic Alzheimer's Disease.

COMMENT This paper is particularly interesting due the effects the authors observed of inhibiting β-secretase in iPSC neurons carrying fAD mutations. The authors observe that fAD mutations in either APP or PSEN1 cause defective degradation of autophagosomes. ...

Michael Lardelli on Novel upregulation of amyloid-β precursor protein (APP) by microRNA-346 via targeting of APP mRNA 5'-untranslated region: Implications in Alzheimer's disease.

COMMENT The intense focus of the AD research community on the function of the APP gene has revealed an astonishingly complex combination of regulatory mechanisms involving transcription, mRNA stability, translation, and protein stability. Many of these mechanisms ...

Michael Lardelli on Questions concerning the role of amyloid-β in the definition, aetiology and diagnosis of Alzheimer's disease.

COMMENT This is a detailed analysis of the role of Aβ in Alzheimer’s disease and the justification for defining Alzheimer’s disease by the presence of Aβ, with supplementary information to extend particular arguments. It traces the historical development of ...

Michael Lardelli on Manganese causes neurotoxic iron accumulation via translational repression of amyloid precursor protein and H-Ferritin.

COMMENT This paper and others recently published (see below) illustrate the critical role played by APP in the regulation of cellular iron homeostasis. APP translation is controlled by the binding to its mRNA of Iron Regulatory Protein 1 (IRP1). Using SH-SY5Y ...

Michael Lardelli on Increased localization of APP-C99 in mitochondria-associated ER membranes causes mitochondrial dysfunction in Alzheimer disease.

COMMENT With this paper, I think Area-Gomez, Schon, and coworkers have made a real advance in our understanding of APP’s role in Alzheimer’s disease. They show that the increased apposition of the ER and mitochondria due to lack of PSEN activity (and as seen in ...

Michael Lardelli on Presenilin-1 Targeted Morpholino Induces Cognitive Deficits, Increased Brain Aβ1-42 and Decreased Synaptic Marker PSD-95 in Zebrafish Larvae.

COMMENT Reading the title of this paper might mislead people to think that there is evidence that zebrafish produce a peptide similar to Aβ. However, while there are two “co-orthologues” of the APP gene in zebrafish (appa and appb), Aβ peptides cleaved from the ...

Michael Lardelli on Analysis of 138 pathogenic mutations in presenilin-1 on the in vitro production of Aβ42 and Aβ40 peptides by γ-secretase.

COMMENT This very significant paper refutes one of the most “beautiful” sets of data supporting the amyloid hypothesis—the correlation between Aβ40:42 ratio and the mean age at onset of AD for FAD mutations in PSEN1. Figure 5 is particularly worthy of note both ...

Michael Lardelli on Transcriptional signatures of brain aging and Alzheimer's disease: What are our rodent models telling us?

COMMENT Hargis and Blalock have analyzed publicly available transcriptome data from humans and rodents and from purported transgenic rodent models of Alzheimer’s disease to assess whether the transgenic rodents are, in fact, modelling the disease. They found good ...

Michael Lardelli on Lodged in Late Endosomes, Presenilin 2 Churns Out Intraneuronal Aβ

COMMENT I was curious to see that this paper did not address the previous observations of Area-Gomez et al. (2009) that a major site of subcellular localization of PSEN2 is the mitochondria-associated membranes of the ER, at least in mouse brain. Since the ...

Michael Lardelli on Pathogenic Presenilin Mutations Generate Aβ43

COMMENT It is fascinating to follow this debate between the teams of De Strooper/Chávez-Gutiérrez and Shen/Kelleher. The technical arguments presented by both teams in the discussion sections of their recent papers in Neuron are valuable information. However, ...

Michael Lardelli on ApoE4 upregulates the activity of mitochondria-associated ER membranes.

COMMENT This very interesting paper continues the work of the Schon laboratory investigating the role that the mitochondrial-associated membranes (MAM) of the endoplasmic reticulum may play in Alzheimer's disease. Schon and co-workers have previously shown ...

Michael Lardelli on Mutant Presenilin Knock-in Mice Mimic Knockouts, Stir Old Debate

COMMENT Xia and co-authors should be commended for examining the function of familial AD (FAD) mutations in PSEN1 in a very physiologically relevant model system. Their observation of loss of γ-secretase activity for FAD mutations engineered into in mouse Psen1 ...

Michael Lardelli on Novel presenilin mutations within Moroccan patients with Early-Onset Alzheimer's Disease.

COMMENT I must admit to being somewhat skeptical about the results presented in this paper and in a sister paper on novel mutations in APP. It seems remarkable (and highly improbable) that the researchers would discover numerous novel frameshift familial AD (FAD) ...

Michael Lardelli on Mitochondria-associated ER membranes in Alzheimer disease.

COMMENT This paper puts in perspective the very interesting results from Eric Schon's laboratory regarding the apparent central role of the mitochondrial-associated membranes (MAM) in Alzheimer's disease. These discoveries revise our understanding of ...