%0 Journal Article %J J Alzheimers Dis %D 2021 %T Possible Role of Activin in the Adiponectin Paradox-Induced Progress of Alzheimer's Disease. %A Hashimoto, Makoto %A Ho, Gilbert %A Sugama, Shuei %A Takenouchi, Takato %A Waragai, Masaaki %A Sugino, Hiromu %A Inoue, Satoshi %A Masliah, Eliezer %X

Accumulating evidence suggests that the adiponectin (APN) paradox might be involved in promoting aging-associated chronic diseases such as Alzheimer's disease (AD). In human brain, APN regulation of the evolvability of amyloidogenic proteins (APs), including amyloid-β (Aβ) and tau, in developmental/reproductive stages, might be paradoxically manifest as APN stimulation of AD through antagonistic pleiotropy in aging. The unique mechanisms underlying APN activity remain unclear, a better understanding of which might provide clues for AD therapy. In this paper, we discuss the possible relevance of activin, a member of transforming growth factor β (TGFβ) superfamily of peptides, to antagonistic pleiotropy effects of APN. Notably, activin, a multiple regulator of cell proliferation and differentiation, as well as an endocrine modulator in reproduction and an organizer in early development, might promote aging-associated disorders, such as inflammation and cancer. Indeed, serum activin, but not serum TGFβ increases during aging. Also, activin/TGFβ signal through type II and type I receptors, both of which are transmembrane serine/threonine kinases, and the serine/threonine phosphorylation of APs, including Aβ 42 serine 8 and αS serine 129, may confer pathological significance in neurodegenerative diseases. Moreover, activin expression is induced by APN in monocytes and hepatocytes, suggesting that activin might be situated downstream of the APN paradox. Finally, a meta-analysis of genome-wide association studies demonstrated that two SNPs relevant to the activin/TGFβ receptor signaling pathways conferred risk for major aging-associated disease. Collectively, activin might be involved in the APN paradox of AD and could be a significant therapeutic target.

%B J Alzheimers Dis %V 81 %P 451-458 %8 2021 May 18 %G eng %N 2 %R 10.3233/JAD-210206 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Adiponectin Paradox as a Therapeutic Target in Alzheimer's Disease. %A Waragai, Masaaki %A Ho, Gilbert %A Takamatsu, Yoshiki %A Wada, Ryoko %A Sugama, Shuei %A Takenouchi, Takato %A Masliah, Eliezer %A Hashimoto, Makoto %X

Despite the apparent neurotoxicity of amyloid-β (Aβ), recent clinical trials of Aβ immunotherapy have not shown any clinical benefit in Alzheimer's disease (AD). Given this, clarification of the next generation therapeutic strategy in AD is warranted. Hypothetically, adiponectin might be involved in promoting amyloidogenic evolvability in reproduction, which may result in the adiponectin paradox through antagonistic pleiotropy mechanism in aging, leading to AD. Accordingly, preventing the adiponectin paradox by suppressing adiponectin signaling might prove therapeutic in AD.

%B J Alzheimers Dis %V 76 %P 1249-1253 %8 2020 %G eng %N 4 %1 https://www.ncbi.nlm.nih.gov/pubmed/32623396?dopt=Abstract %R 10.3233/JAD-200416 %0 Journal Article %J J Alzheimers Dis %D 2019 %T The Effects of APOE4 on Mitochondrial Dynamics and Proteins in vivo. %A Simonovitch, Shira %A Schmukler, Eran %A Masliah, Eliezer %A Pinkas-Kramarski, Ronit %A Michaelson, Daniel M %X

This study examined the effects of apolipoprotein E4 (APOE4), the most prevalent genetic risk factor for Alzheimer's disease (AD), on proteins involved in mitochondrial dynamics and autophagy, in the hippocampus of targeted replacement mice. Immunohistochemical measurements revealed that the levels of the mitochondrial fusion-mediating protein, MFN1, were higher, whereas those of corresponding fission-regulating protein, DRP-1, were lower in the hippocampus of ApoE4 mice than in the corresponding ApoE3 mice, indicating that APOE4 is associated with increased mitochondrial fusion and decreased fission. A similar ApoE4-driven decrease in DRP-1 was also observed in AD brains. The levels of the mitochondrial proteins COX1 and Tom40, were higher in the ApoE4 mice, which is consistent with the increased fusion. Measurements of the levels of cleaved PINK1 and parkin, which mark and target mitochondria for mitophagic degradation, revealed lower levels of cleaved PINK1, suggesting reduced mitochondrial membrane potential, and higher levels of parkin in the hippocampus of ApoE4 compared with the ApoE3 mice, indicating altered mitophagy. The levels of the ubiquitin-binding scaffold protein, p62/SQSTM1, which directs selected cargo to the autophagosomes, were also higher in the ApoE4 mice. These findings suggest that APOE4 is associated with enhanced mitochondrial fusion and decreased fission. Additionally, the results indicate that the mitophagy/autophagy is reduced in ApoE4 mice, resulting in higher levels of proteins such as parkin and p62, which are normally degraded during this process. Taken together, these results suggest a novel mechanism that may underlie the pathological effects of APOE4 and indicate that use of APOE4 genotyping could pave the way for identification of novel APOE4-related therapeutic targets.

%B J Alzheimers Dis %V 70 %P 861-875 %8 2019 Aug 3 %G eng %N 3 %R 10.3233/JAD-190074 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Remembering Robert D. Terry at a Time of Change in the World of Alzheimer's Disease. %A Terry, Nickolas %A Masliah, Alberto %A Overk, Cassia %A Masliah, Eliezer %B J Alzheimers Dis %V 70 %P 621-628 %8 2019 Aug 3 %G eng %N 3 %R 10.3233/JAD-190518 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Dale Schenk One Year Anniversary: Fighting to Preserve the Memories. %A Overk, Cassia %A Masliah, Eliezer %X

It has been a year since we lost Dale Schenk on September 30, 2016. Dale's visionary work resulted in the remarkable discovery in 1999 that an experimental amyloid-β (Aβ) vaccine reduced the neurodegeneration in a transgenic model of Alzheimer's disease (AD). Following Dale's seminal work, several active and passive immunotherapies have since been developed and tested in the clinic for AD, Parkinson's disease (PD), and other neurodegenerative disorders. Here we provide a brief overview of the current state of development of immunotherapy for AD, PD, and other neurodegenerative disorders in the context of this anniversary. The next steps in the development of immunotherapies will require combinatorial approaches mixing antibodies against various targets (e.g., Aβ, α-syn, Tau, and TDP43) with small molecules that block toxicity, aggregation, inflammation, and promote cell survival.

%B J Alzheimers Dis %V 62 %P 1-13 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29439357?dopt=Abstract %R 10.3233/JAD-171071 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Evolvability of Amyloidogenic Proteins in Human Brain. %A Hashimoto, Makoto %A Ho, Gilbert %A Sugama, Shuei %A Takamatsu, Yoshiki %A Shimizu, Yuka %A Takenouchi, Takato %A Waragai, Masaaki %A Masliah, Eliezer %X

 Currently, the physiological roles of amyloidogenic proteins (APs) in human brain, such as amyloid-β and α-synuclein, are elusive. Given that many APs arose by gene duplication and have been resistant against the pressures of natural selection, APs may be associated with some functions that are advantageous for survival of offspring. Nonetheless, evolvability is the sole physiological quality of APs that has been characterized in microorganisms such as yeast. Since yeast and human brain may share similar strategies in coping with diverse range of critical environmental stresses, the objective of this paper was to discuss the potential role of evolvability of APs in aging-associated neurodegenerative disorders, including Alzheimer's disease and Parkinson's disease. Given the heterogeneity of APs in terms of structure and cytotoxicity, it is argued that APs might be involved in preconditioning against diverse stresses in human brain. It is further speculated that these stress-related APs, most likely protofibrillar forms, might be transmitted to offspring via the germline, conferring preconditioning against forthcoming stresses. Thus, APs might represent a vehicle for the inheritance of the acquired characteristics against environmental stresses. Curiously, such a characteristic of APs is reminiscent of Charles Darwin's 'gemmules', imagined molecules of heritability described in his pangenesis theory. We propose that evolvability might be a physiological function of APs during the reproductive stage and neurodegenerative diseases could be a by-product effect manifested later in aging. Collectively, our evolvability hypothesis may play a complementary role in the pathophysiology of APs with the conventional amyloid cascade hypothesis.

%B J Alzheimers Dis %V 62 %P 73-83 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29439348?dopt=Abstract %R 10.3233/JAD-170894 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Increased Vulnerability of the Hippocampus in Transgenic Mice Overexpressing APP and Triple Repeat Tau. %A Arner, Andrew %A Rockenstein, Edward %A Mante, Michael %A Florio, Jazmin %A Masliah, Deborah %A Salehi, Bahar %A Adame, Anthony %A Overk, Cassia %A Masliah, Eliezer %A Rissman, Robert A %K Alzheimer Disease %K Amyloid beta-Peptides %K Animals %K Disease Models, Animal %K Female %K Glycogen Synthase Kinase 3 %K Hippocampus %K Humans %K Male %K Mice %K Mice, Transgenic %K Neocortex %K tau Proteins %K Tauopathies %X

Alzheimer's disease (AD) is the most common tauopathy, characterized by progressive accumulation of amyloid-β (Aβ) and hyperphosphorylated tau. While pathology associated with the 4-repeat (4R) tau isoform is more abundant in corticobasal degeneration and progressive supranuclear palsy, both 3R and 4R tau isoforms accumulate in AD. Many studies have investigated interactions between Aβ and 4R tau in double transgenic mice, but few, if any, have examined the effects of Aβ with 3R tau. To examine this relationship, we crossed our APP751 mutant line with our recently characterized 3R tau mutant model to create a bigenic line (hAPP-3RTau) to model AD neuropathology. Mice were analyzed at 3 and 6 months of age for pathological and behavioral endpoints. While both the 3RTau and the hAPP-3RTau mice showed neuronal loss, increased tau aggregation, Aβ plaques and exhibited more behavioral deficits compared to the non-tg control, the bigenic mice often displaying relatively worsening levels. We found that even in young animals we found that the presence of APP/Aβ increased the accumulation of 3R tau in the neocortex and hippocampus. This observation was accompanied by activation of GSK3 and neurodegeneration in the neocortex and CA1 region. These results suggest that in addition to 4R tau, APP/Aβ may also enhance accumulation of 3R tau, a process which may be directly relevant to pathogenic pathways in AD. Our results demonstrate that this bigenic model closely parallels the pathological course of AD and may serve as a valuable model for testing new pharmacological interventions.

%B J Alzheimers Dis %V 61 %P 1201-1219 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29332037?dopt=Abstract %R 10.3233/JAD-170388 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Impaired Autophagy in APOE4 Astrocytes. %A Simonovitch, Shira %A Schmukler, Eran %A Bespalko, Alina %A Iram, Tal %A Frenkel, Dan %A Holtzman, David M %A Masliah, Eliezer %A Michaelson, Danny M %A Pinkas-Kramarski, Ronit %K Amyloid beta-Peptides %K Animals %K Apolipoprotein E3 %K Apolipoprotein E4 %K Astrocytes %K Autophagy %K Brain %K Cells, Cultured %K Central Nervous System Agents %K Chloroquine %K Disease Models, Animal %K Humans %K Mice, Transgenic %K Plaque, Amyloid %K Sirolimus %K Time Factors %X

Alzheimer's disease (AD) is the most prevalent form of dementia in elderly. Genetic studies revealed allelic segregation of the apolipoprotein E (ApoE) gene in sporadic AD and in families with higher risk of AD. The mechanisms underlying the pathological effects of ApoE4 are not yet entirely clear. Several studies indicate that autophagy, which plays an important role in degradation pathways of proteins, organelles and protein aggregates, may be impaired in AD. In the present study, we investigated the effects of ApoE4 versus the ApoE3 isoform on the process of autophagy in mouse-derived astrocytes. The results obtained reveal that under several autophagy-inducing conditions, astrocytes expressing ApoE4 exhibit lower autophagic flux compared to astrocytes expressing ApoE3. Using an in situ model, we examined the role of autophagy and the effects thereon of ApoE4 in the elimination of Aβ plaques from isolated brain sections of transgenic 5xFAD mice. This revealed that ApoE4 astrocytes eliminate Aβ plaques less effectively than the corresponding ApoE3 astrocytes. Additional experiments showed that the autophagy inducer, rapamycin, enhances Aβ plaque degradation by ApoE4 astrocytes whereas the autophagy inhibitor, chloroquine, blocks Aβ plaque degradation by ApoE3 astrocytes. Taken together, these findings show that ApoE4 impairs autophagy in astrocyte cultures and that this effect is associated with reduced capacity to clear Aβ plaques. This suggests that impaired autophagy may play a role in mediating the pathological effects of ApoE4 in AD.

%B J Alzheimers Dis %V 51 %P 915-27 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26923027?dopt=Abstract %R 10.3233/JAD-151101 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Possible Involvement of Adiponectin, the Anti-Diabetes Molecule, in the Pathogenesis of Alzheimer's Disease. %A Waragai, Masaaki %A Adame, Anthony %A Trinh, Ivy %A Sekiyama, Kazunari %A Takamatsu, Yoshiki %A Une, Kaori %A Masliah, Eliezer %A Hashimoto, Makoto %X

Adiponectin (APN) is protective in animal models of neurodegenerative diseases, but the role of APN in human brain has not been established. Using an enzyme-linked immunosorbent assay, we found that APN was significantly decreased in cerebrospinal fluid (CSF) of patients with Alzheimer's disease (AD), compared to those in patients with mild cognitive impairment (MCI) and in normal controls (NC), despite elevation of APN in serum of patients with MCI and AD compared to that in NC. The discrepancy of CSF APN from serum APN in AD may suggest some critical actions of APN in the pathogenesis of AD. Indeed, it was histologically observed that APN was co-localized with tau in neurofibrillary tangles and immunoblot analysis showed that the functional trimers of APN were significantly decreased in AD compared to those in NC. Collectively, a loss of function of APN may be involved in the pathogenesis of AD.

%B J Alzheimers Dis %V 52 %P 1453-9 %8 2016 Apr 08 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27079710?dopt=Abstract %R 10.3233/JAD-151116 %0 Journal Article %J Alzheimers Dement %D 2012 %T National Institute on Aging-Alzheimer's Association guidelines for the neuropathologic assessment of Alzheimer's disease. %A Hyman, Bradley T %A Phelps, Creighton H %A Beach, Thomas G %A Bigio, Eileen H %A Cairns, Nigel J %A Carrillo, Maria C %A Dickson, Dennis W %A Duyckaerts, Charles %A Frosch, Matthew P %A Masliah, Eliezer %A Mirra, Suzanne S %A Nelson, Peter T %A Schneider, Julie A %A Thal, Dietmar Rudolf %A Thies, Bill %A Trojanowski, John Q %A Vinters, Harry V %A Montine, Thomas J %K Alzheimer Disease %K Brain %K Consensus Development Conferences, NIH as Topic %K Humans %K National Institute on Aging (U.S.) %K Practice Guidelines as Topic %K Societies, Medical %K United States %X

A consensus panel from the United States and Europe was convened recently to update and revise the 1997 consensus guidelines for the neuropathologic evaluation of Alzheimer's disease (AD) and other diseases of brain that are common in the elderly. The new guidelines recognize the pre-clinical stage of AD, enhance the assessment of AD to include amyloid accumulation as well as neurofibrillary change and neuritic plaques, establish protocols for the neuropathologic assessment of Lewy body disease, vascular brain injury, hippocampal sclerosis, and TDP-43 inclusions, and recommend standard approaches for the workup of cases and their clinico-pathologic correlation.

%B Alzheimers Dement %V 8 %P 1-13 %8 2012 Jan %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/22265587?dopt=Abstract %R 10.1016/j.jalz.2011.10.007