%0 Journal Article %J J Alzheimers Dis %D 2023 %T An Alternative View of Familial Alzheimer's Disease Genetics. %A Lardelli, Michael %K Alzheimer Disease %K Amyloid beta-Peptides %K Amyloid beta-Protein Precursor %K Amyloid Precursor Protein Secretases %K Humans %K Iron %K Mutation %K Presenilin-1 %X

Probabilistic and parsimony-based arguments regarding available genetics data are used to propose that Hardy and Higgin's amyloid cascade hypothesis is valid but is commonly interpreted too narrowly to support, incorrectly, the primacy of the amyloid-β peptide (Aβ) in driving Alzheimer's disease pathogenesis. Instead, increased activity of the βCTF (C99) fragment of AβPP is the critical pathogenic determinant altered by mutations in the APP gene. This model is consistent with the regulation of APP mRNA translation via its 5' iron responsive element. Similar arguments support that the pathological effects of familial Alzheimer's disease mutations in the genes PSEN1 and PSEN2 are not exerted directly via changes in AβPP cleavage to produce different ratios of Aβ length. Rather, these mutations likely act through effects on presenilin holoprotein conformation and function, and possibly the formation and stability of multimers of presenilin holoprotein and/or of the γ-secretase complex. All fAD mutations in APP, PSEN1, and PSEN2 likely find unity of pathological mechanism in their actions on endolysosomal acidification and mitochondrial function, with detrimental effects on iron homeostasis and promotion of "pseudo-hypoxia" being of central importance. Aβ production is enhanced and distorted by oxidative stress and accumulates due to decreased lysosomal function. It may act as a disease-associated molecular pattern enhancing oxidative stress-driven neuroinflammation during the cognitive phase of the disease.

%B J Alzheimers Dis %V 96 %P 13-39 %8 2023 %G eng %N 1 %R 10.3233/JAD-230313 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Iron Responsive Element-Mediated Responses to Iron Dyshomeostasis in Alzheimer's Disease. %A Hin, Nhi %A Newman, Morgan %A Pederson, Stephen %A Lardelli, Michael %X

BACKGROUND: Iron trafficking and accumulation is associated with Alzheimer's disease (AD) pathogenesis. However, the role of iron dyshomeostasis in early disease stages is uncertain. Currently, gene expression changes indicative of iron dyshomeostasis are not well characterized, making it difficult to explore these in existing datasets.

OBJECTIVE: To identify sets of genes predicted to contain iron responsive elements (IREs) and use these to explore possible iron dyshomeostasis-associated gene expression responses in AD.

METHODS: Comprehensive sets of genes containing predicted IRE or IRE-like motifs in their 3' or 5' untranslated regions (UTRs) were identified in human, mouse, and zebrafish reference transcriptomes. Further analyses focusing on these genes were applied to a range of cultured cell, human, mouse, and zebrafish gene expression datasets.

RESULTS: IRE gene sets are sufficiently sensitive to distinguish not only between iron overload and deficiency in cultured cells, but also between AD and other pathological brain conditions. Notably, changes in IRE transcript abundance are among the earliest observable changes in zebrafish familial AD (fAD)-like brains, preceding other AD-typical pathologies such as inflammatory changes. Unexpectedly, while some IREs in the 3' untranslated regions of transcripts show significantly increased stability under iron deficiency in line with current assumptions, many such transcripts instead display decreased stability, indicating that this is not a generalizable paradigm.

CONCLUSION: Our results reveal IRE gene expression changes as early markers of the pathogenic process in fAD and are consistent with iron dyshomeostasis as an important driver of this disease. Our work demonstrates how differences in the stability of IRE-containing transcripts can be used to explore and compare iron dyshomeostasis-associated gene expression responses across different species, tissues, and conditions.

%B J Alzheimers Dis %V 84 %P 1597-1630 %8 2021 Dec 07 %G eng %N 4 %R 10.3233/JAD-210200 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Relevance of a Truncated PRESENILIN 2 Transcript to Alzheimer's Disease and Neurodegeneration. %A Moussavi Nik, Seyyed Hani %A Porter, Tenielle %A Newman, Morgan %A Bartlett, Benjamin %A Khan, Imran %A Sabale, Miheer %A Eccles, Melissa %A Woodfield, Amy %A Groth, David %A Doré, Vincent %A Villemagne, Victor L %A Masters, Colin L %A Martins, Ralph N %A Laws, Simon M %A Lardelli, Michael %A Verdile, Giuseppe %X

BACKGROUND: The PRESENILIN genes (PSEN1, PSEN2) encoding for their respective proteins have critical roles in many aspects of Alzheimer's disease (AD) pathogenesis. The PS2V transcript of PSEN2 encodes a truncated protein and is upregulated in AD brains; however, its relevance to AD and disease progression remains to be determined.

OBJECTIVE: Assess transcript levels in postmortem AD and non-AD brain tissue and in lymphocytes collected under the Australian Imaging Biomarker and Lifestyle (AIBL) study.

METHODS: Full length PSEN2 and PS2V transcript levels were assessed by quantitative digital PCR in postmortem brain tissue (frontal cortex and hippocampus) from control, AD, frontotemporal dementia (FTD), and Lewy body dementia (LBD). Transcript levels were also assessed in lymphocytes obtained from the Perth subset of the AIBL study (n = 160). Linear regression analysis was used to assess correlations between transcript copy number and brain volume and neocortical amyloid load.

RESULTS: PS2V levels increased in AD postmortem brain but PS2V was also present at significant levels in FTD and LBD brains. PS2V transcript was detected in lymphocytes and PS2V/PSEN2 ratios were increased in mild cognitive impairment (p = 0.024) and AD (p = 0.019) groups compared to control group. Increased ratios were significantly correlated with hippocampal volumes only (n = 62, β= -0.269, p = 0.03).

CONCLUSION: Taken together, these results suggest that PS2V may be a marker of overall neurodegeneration.

%B J Alzheimers Dis %V 80 %P 1479-1489 %8 2021 Apr 20 %G eng %N 4 %R 10.3233/JAD-201133 %0 Journal Article %J J Alzheimers Dis %D 2018 %T A Review of the Familial Alzheimer's Disease Locus PRESENILIN 2 and Its Relationship to PRESENILIN 1. %A Jiang, Haowei %A Jayadev, Suman %A Lardelli, Michael %A Newman, Morgan %X

PRESENILIN 1 (PSEN1) and PRESENILIN 2 (PSEN2) genes are loci for mutations causing familial Alzheimer's disease (fAD). However, the function of these genes and how they contribute to fAD pathogenesis has not been fully determined. This review provides a summary of the overlapping and independent functions of the PRESENILINS with a focus on the lesser studied PSEN2. As a core component of the γ-secretase complex, the PSEN2 protein is involved in many γ-secretase-related physiological activities, including innate immunity, Notch signaling, autophagy, and mitochondrial function. These physiological activities have all been associated with AD progression, indicating that PSEN2 plays a particular role in AD pathogenesis.

%B J Alzheimers Dis %V 66 %P 1323-1339 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30412492?dopt=Abstract %R 10.3233/JAD-180656 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Evidence For and Against a Pathogenic Role of Reduced γ-Secretase Activity in Familial Alzheimer's Disease. %A Jayne, Tanya %A Newman, Morgan %A Verdile, Giuseppe %A Sutherland, Greg %A Münch, Gerald %A Musgrave, Ian %A Moussavi Nik, Seyyed Hani %A Lardelli, Michael %X

The majority of mutations causing familial Alzheimer's disease (fAD) have been found in the gene PRESENILIN1 (PSEN1) with additional mutations in the related gene PRESENILIN2 (PSEN2). The best characterized function of PRESENILIN (PSEN) proteins is in γ-secretase enzyme activity. One substrate of γ-secretase is encoded by the gene AMYLOID BETA A4 PRECURSOR PROTEIN (AβPP/APP) that is a fAD mutation locus. AβPP is the source of the amyloid-β (Aβ) peptide enriched in the brains of people with fAD or the more common, late onset, sporadic form of AD, sAD. These observations have resulted in a focus on γ-secretase activity and Aβ as we attempt to understand the molecular basis of AD pathology. In this paper we briefly review some of the history of research on γ-secretase in AD. We then discuss the main ideas regarding the role of γ-secretase and the PSEN genes in this disease. We examine the significance of the "fAD mutation reading frame preservation rule" that applies to PSEN1 and PSEN2 (and AβPP) and look at alternative roles for AβPP and Aβ in fAD. We present a case for an alternative interpretation of published data on the role of γ-secretase activity and fAD-associated mutations in AD pathology. Evidence supports a "PSEN holoprotein multimer hypothesis" where PSEN fAD mutations generate mutant PSEN holoproteins that multimerize with wild type holoprotein and dominantly interfere with an AD-critical function(s) such as autophagy or secretion of Aβ. Holoprotein multimerization may be required for the endoproteolysis that activates PSENs' γ-secretase activity.

%B J Alzheimers Dis %V 52 %P 781-99 %8 2016 Apr 04 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27060961?dopt=Abstract %R 10.3233/JAD-151186 %0 Journal Article %J J Alzheimers Dis %D 2016 %T The Zebrafish Equivalent of Alzheimer's Disease-Associated PRESENILIN Isoform PS2V Regulates Inflammatory and Other Responses to Hypoxic Stress. %A Ebrahimie, Esmaeil %A Moussavi Nik, Seyyed Hani %A Newman, Morgan %A Van Der Hoek, Mark %A Lardelli, Michael %X

Dominant mutations in the PRESENILIN genes PSEN1 and PSEN2 cause familial Alzheimer's disease (fAD) that usually shows onset before 65 years of age. In contrast, genetic variation at the PSEN1 and PSEN2 loci does not appear to contribute to risk for the sporadic, late onset form of the disease (sAD), leading to doubts that these genes play a role in the majority of AD cases. However, a truncated isoform of PSEN2, PS2V, is upregulated in sAD brains and is induced by hypoxia and high cholesterol intake. PS2V can increase γ-secretase activity and suppress the unfolded protein response (UPR), but detailed analysis of its function has been hindered by lack of a suitable, genetically manipulable animal model since mice and rats lack this PRESENILIN isoform. We recently showed that zebrafish possess an isoform, PS1IV, that is cognate to human PS2V. Using an antisense morpholino oligonucleotide, we can block specifically the induction of PS1IV that normally occurs under hypoxia. Here, we exploit this ability to identify gene regulatory networks that are modulated by PS1IV. When PS1IV is absent under hypoxia-like conditions, we observe changes in expression of genes controlling inflammation (particularly sAD-associated IL1B and CCR5), vascular development, the UPR, protein synthesis, calcium homeostasis, catecholamine biosynthesis, TOR signaling, and cell proliferation. Our results imply an important role for PS2V in sAD as a component of a pathological mechanism that includes hypoxia/oxidative stress and support investigation of the role of PS2V in other diseases, including schizophrenia, when these are implicated in the pathology.

%B J Alzheimers Dis %V 52 %P 581-608 %8 2016 Mar 31 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27031468?dopt=Abstract %R 10.3233/JAD-150678