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Interaction between KLOTHO-VS Heterozygosity and APOE ε4 Allele Predicts Rate of Cognitive Decline in Late-Onset Alzheimer's Disease

Chen, Xi Richard; Shao, Yongzhao; Sadowski, Martin J
PMCID:10137709
PMID: 37107675
ISSN: 2073-4425
CID: 5465462

Forty-hertz light stimulation does not entrain native gamma oscillations in Alzheimer's disease model mice

Soula, Marisol; Martín-Ávila, Alejandro; Zhang, Yiyao; Dhingra, Annika; Nitzan, Noam; Sadowski, Martin J; Gan, Wen-Biao; Buzsáki, György
There is a demand for noninvasive methods to ameliorate disease. We investigated whether 40-Hz flickering light entrains gamma oscillations and suppresses amyloid-β in the brains of APP/PS1 and 5xFAD mouse models of Alzheimer's disease. We used multisite silicon probe recording in the visual cortex, entorhinal cortex or the hippocampus and found that 40-Hz flickering simulation did not engage native gamma oscillations in these regions. Additionally, spike responses in the hippocampus were weak, suggesting 40-Hz light does not effectively entrain deep structures. Mice avoided 40-Hz flickering light, associated with elevated cholinergic activity in the hippocampus. We found no reliable changes in plaque count or microglia morphology by either immunohistochemistry or in vivo two-photon imaging following 40-Hz stimulation, nor reduced levels of amyloid-β 40/42. Thus, visual flicker stimulation may not be a viable mechanism for modulating activity in deep structures.
PMID: 36879142
ISSN: 1546-1726
CID: 5432632

Peroxiredoxin 6 Regulates Glia Toxicity in Tau Mediated Neurodegeneration

Pankiewicz, Joanna E; Lizinczyk, Anita M; Franco, Leor A; Sadowski, Martin J
ORIGINAL:0016569
ISSN: 1552-5279
CID: 5435752

Absence of Apolipoprotein E Exacerbates Prion Pathology and Promote Microglial Mediated Neurodegeneration

Lizinczyk, Anita M; Pankiewicz, Joanna E; Franco, Leor A; Diaz, Jenny R; Ariza, Mtichell Marta; Sadowski, Martin J
ORIGINAL:0016570
ISSN: 1552-5279
CID: 5435762

Functional Outcomes of a Comprehensive, Individualized, Person-Centered Management Program in Advanced Alzheimer"™s Disease(AD): Results from a 52-Week Randomized Controlled Trial

Kenowsky, Sunnie; Shao, Yongzhao; Zhang, Qiao; Dafflisio, Gianna; Vedvyas, Alok; Vedvyas, Gaurav; Golomb, James B.; Torossian, Carol; Marsh, Karyn; Heller, Sloane; Sadowski, Martin J.; Reisberg, Barry
Background: We conducted a 28-week, single-blind, randomized, controlled trial of the efficacy of Comprehensive, Individualized, Person-Centered Management (CI-PCM) and memantine treatment (Reisberg et al., Dement Geriatr Cogn Disord, 2017) in advanced AD persons. CI-PCM and memantine was approximately 7.5 times more beneficial to AD persons on the Functional Assessment Staging Tool (FAST) (Kenowsky et. al., Alzheimer"™s and Dementia, 2017) than to AD persons who received memantine alone in the memantine FDA approval pivotal trial conducted by Reisberg et. al., (NEJM 2003). We also conducted a 24-week extension study. Herein, we report the difference in functional outcomes between the CI-PCM and Usual Community Care (UCC+FC) groups at 52-weeks on the FAST and the ADCS-ADLSev-Abv. See Figures 1 and 2. Method: After screening, 20 eligible subject-carepartner dyads were randomized equally to the CI-PCM and UCC+FC groups. All 20 dyads completed the 28-week study and entered the 24-week extension study. One subject in the UCC+FC group died during the extension study. The FAST and ADCS-ADLsev-abv were conducted at baseline, and weeks 4, 12, 28, and 52. P values were calculated using the Wilcoxon Mann Whitney test. Result: The mean FAST total score from baseline (6.6±0.1SE) to week 52 (6.5±0.01SE) showed an improvement of functional limitations in the CI-PCM group. The mean FAST total score for the UCC+FC group showed a functional decline from baseline (6.6±0.1SE) to week 52 (6.8±0.1SE), displaying a robustly significant difference between the two groups (p<0.0014). The mean ADCS-ADL-sev-abv total score for the CI-PCM group demonstrated a 20.9% improvement in functioning from baseline (15.3±2.0SE) to week 52 (18.5±2.5SE). The mean ADCS-ADL-sev-abv total score for the UCC+FC group showed a decline of 48.6% from baseline (14.8±2.1SE) to week 52 (7.6±2.3SE), indicating a significant difference between the two groups (p<0.009). Conclusion: The CI-PCM program is the only evidenced-based treatment to date that can significantly improve and reverse functional deterioration in advanced AD persons. The functional success of the CI-PCM program may primarily be attributed to care partners learning to memory coach AD persons to perform daily activities such as bathing, dressing, feeding and toileting themselves, and to become/maintain urinary and fecal continence.
SCOPUS:85144362721
ISSN: 1552-5260
CID: 5393842

Apolipoprotein E4 Effects a Distinct Transcriptomic Profile and Dendritic Arbor Characteristics in Hippocampal Neurons Cultured in vitro

Diaz, Jenny R; Martá-Ariza, Mitchell; Khodadadi-Jamayran, Alireza; Heguy, Adriana; Tsirigos, Aristotelis; Pankiewicz, Joanna E; Sullivan, Patrick M; Sadowski, Martin J
The APOE gene is diversified by three alleles ε2, ε3, and ε4 encoding corresponding apolipoprotein (apo) E isoforms. Possession of the ε4 allele is signified by increased risks of age-related cognitive decline, Alzheimer's disease (AD), and the rate of AD dementia progression. ApoE is secreted by astrocytes as high-density lipoprotein-like particles and these are internalized by neurons upon binding to neuron-expressed apoE receptors. ApoE isoforms differentially engage neuronal plasticity through poorly understood mechanisms. We examined here the effects of native apoE lipoproteins produced by immortalized astrocytes homozygous for ε2, ε3, and ε4 alleles on the maturation and the transcriptomic profile of primary hippocampal neurons. Control neurons were grown in the presence of conditioned media from Apoe -/- astrocytes. ApoE2 and apoE3 significantly increase the dendritic arbor branching, the combined neurite length, and the total arbor surface of the hippocampal neurons, while apoE4 fails to produce similar effects and even significantly reduces the combined neurite length compared to the control. ApoE lipoproteins show no systemic effect on dendritic spine density, yet apoE2 and apoE3 increase the mature spines fraction, while apoE4 increases the immature spine fraction. This is associated with opposing effects of apoE2 or apoE3 and apoE4 on the expression of NR1 NMDA receptor subunit and PSD95. There are 1,062 genes differentially expressed across neurons cultured in the presence of apoE lipoproteins compared to the control. KEGG enrichment and gene ontology analyses show apoE2 and apoE3 commonly activate expression of genes involved in neurite branching, and synaptic signaling. In contrast, apoE4 cultured neurons show upregulation of genes related to the glycolipid metabolism, which are involved in dendritic spine turnover, and those which are usually silent in neurons and are related to cell cycle and DNA repair. In conclusion, our work reveals that lipoprotein particles comprised of various apoE isoforms differentially regulate various neuronal arbor characteristics through interaction with neuronal transcriptome. ApoE4 produces a functionally distinct transcriptomic profile, which is associated with attenuated neuronal development. Differential regulation of neuronal transcriptome by apoE isoforms is a newly identified biological mechanism, which has both implication in the development and aging of the CNS.
PMCID:9099260
PMID: 35572125
ISSN: 1663-4365
CID: 5232812

Absence of Apolipoprotein E is associated with exacerbation of prion pathology and promotes microglial neurodegenerative phenotype

Pankiewicz, Joanna E; Lizińczyk, Anita M; Franco, Leor A; Diaz, Jenny R; Martá-Ariza, Mitchell; Sadowski, Martin J
Prion diseases or prionoses are a group of rapidly progressing and invariably fatal neurodegenerative diseases. The pathogenesis of prionoses is associated with self-replication and connectomal spread of PrPSc, a disease specific conformer of the prion protein. Microglia undergo activation early in the course of prion pathogenesis and exert opposing roles in PrPSc mediated neurodegeneration. While clearance of PrPSc and apoptotic neurons have disease-limiting effect, microglia-driven neuroinflammation bears deleterious consequences to neuronal networks. Apolipoprotein (apo) E is a lipid transporting protein with pleiotropic functions, which include controlling of the phagocytic and inflammatory characteristics of activated microglia in neurodegenerative diseases. Despite the significance of microglia in prion pathogenesis, the role of apoE in prionoses has not been established. We showed here that infection of wild type mice with 22L mouse adapted scrapie strain is associated with significant increase in the total brain apoE protein and mRNA levels and also with a conspicuous cell-type shift in the apoE expression. There is reduced expression of apoE in activated astrocytes and marked upregulation of apoE expression by activated microglia. We also showed apoE ablation exaggerates PrPSc mediated neurodegeneration. Apoe-/- mice have shorter disease incubation period, increased load of spongiform lesion, pronounced neuronal loss, and exaggerated astro and microgliosis. Astrocytes of Apoe-/- mice display salient upregulation of transcriptomic markers defining A1 neurotoxic astrocytes while microglia show upregulation of transcriptomic markers characteristic for microglial neurodegenerative phenotype. There is impaired clearance of PrPSc and dying neurons by microglia in Apoe-/- mice along with increased level of proinflammatory cytokines. Our work indicates that apoE absence renders clearance of PrPSc and dying neurons by microglia inefficient, while the excess of neuronal debris promotes microglial neurodegenerative phenotype aggravating the vicious cycle of neuronal death and neuroinflammation.
PMCID:8474943
PMID: 34565486
ISSN: 2051-5960
CID: 5061562

Segmented Linear Mixed Model Analysis Reveals Association of the APOEɛ4 Allele with Faster Rate of Alzheimer's Disease Dementia Progression

Richard Chen, X; Shao, Yongzhao; Sadowski, Martin J
BACKGROUND:APOEɛ4 allele carriers present with increased risk for late-onset Alzheimer's disease (AD), show cognitive symptoms at earlier age, and are more likely to transition from mild cognitive impairment (MCI) to dementia but despite this, it remains unclear whether or not the ɛ4 allele controls the rate of disease progression. OBJECTIVE:To determine effects of the ɛ4 allele on rates of cognitive decline and brain atrophy during MCI and dementia stages of AD. METHODS:A segmented linear mixed model was chosen for longitudinal modeling of cognitive and brain volumetric data of 73 ɛ3/ɛ3, 99 ɛ3/ɛ4, and 39 ɛ4/ɛ4 Alzheimer's Disease Neuroimaging Initiative participants who transitioned during the study from MCI to AD dementia. RESULTS:ɛ4 carriers showed faster decline on MMSE, ADAS-11, CDR-SB, and MoCA scales, with the last two measures showing significant ɛ4 allele-dose effects after dementia transition but not during MCI. The ɛ4 effect was more prevalent in younger participants and in females. ɛ4 carriers also demonstrated faster rates of atrophy of the whole brain, the hippocampus, the entorhinal cortex, the middle temporal gyrus, and expansion of the ventricles after transitioning to dementia but not during MCI. CONCLUSION/CONCLUSIONS:Possession of the ɛ4 allele is associated with a faster progression of dementia due to AD. Our observations support the notion that APOE genotype not only controls AD risk but also differentially regulates mechanisms of neurodegeneration underlying disease advancement. Furthermore, our findings carry significance for AD clinical trial design.
PMID: 34120907
ISSN: 1875-8908
CID: 4911232

Peroxiredoxin 6 mediates protective function of astrocytes in Aβ proteostasis

Pankiewicz, Joanna E; Diaz, Jenny R; Martá-Ariza, Mitchell; Lizińczyk, Anita M; Franco, Leor A; Sadowski, Martin J
BACKGROUND:) activities involved in repair of oxidatively damaged cell membrane lipids and cellular signaling. In the CNS, PRDX6 is uniquely expressed by astrocytes and its exact function remains unexplored. METHODS:AD transgenic mice were once crossed to mice overexpressing wild-type Prdx6 allele or to Prdx6 knock out mice. Aβ pathology and associated neuritic degeneration were assessed in mice aged 10 months. Laser scanning confocal microscopy was used to characterize Aβ plaque morphology and activation of plaque-associated astrocytes and microglia. Effect of Prdx6 gene dose on plaque seeding was assessed in mice aged six months. RESULTS:AD transgenic mice promotes selective enticement of astrocytes to Aβ plaques and penetration of plaques by astrocytic processes along with increased number and phagocytic activation of periplaque microglia. This effects suppression of nascent plaque seeding and remodeling of mature plaques consequently curtailing brain Aβ load and Aβ-associated neuritic degeneration. Conversely, Prdx6 haplodeficiency attenuates astro- and microglia activation around Aβ plaques promoting Aβ deposition and neuritic degeneration. CONCLUSIONS:We identify here PRDX6 as an important factor regulating response of astrocytes toward Aβ plaques. Demonstration that phagocytic activation of periplaque microglia vary directly with astrocytic PRDX6 expression level implies previously unappreciated astrocyte-guided microglia effect in Aβ proteostasis. Our showing that upregulation of PRDX6 attenuates Aβ pathology may be of therapeutic relevance for AD.
PMID: 32907613
ISSN: 1750-1326
CID: 4589342

FAM222A encodes a protein which accumulates in plaques in Alzheimer's disease

Yan, Tingxiang; Liang, Jingjing; Gao, Ju; Wang, Luwen; Fujioka, Hisashi; Zhu, Xiaofeng; Wang, Xinglong; Weiner, Michael W; Schuff, Norbert; Rosen, Howard J; Miller, Bruce L; Perry, David; Aisen, Paul; Toga, Arthur W; Jimenez, Gustavo; Donohue, Michael; Gessert, Devon; Harless, Kelly; Salazar, Jennifer; Cabrera, Yuliana; Walter, Sarah; Hergesheimer, Lindsey; Toga, Arthur W; Crawford, Karen; Neu, Scott; Schneider, Lon S; Pawluczyk, Sonia; Becerra, Mauricio; Teodoro, Liberty; Spann, Bryan M; Aisen, Paul; Petersen, Ronald; Jack, Clifford R; Bernstein, Matthew; Borowski, Bret; Gunter, Jeff; Senjem, Matt; Vemuri, Prashanthi; Jones, David; Kantarci, Kejal; Ward, Chad; Mason, Sara S; Albers, Colleen S; Knopman, David; Johnson, Kris; Graff-Radford, Neill R; Parfitt, Francine; Poki-Walker, Kim; Jagust, William; Landau, Susan; Trojanowki, John Q; Shaw, Leslie M; Karlawish, Jason H; Wolk, David A; Vaishnavi, Sanjeev; Clark, Christopher M; Arnold, Steven E; Lee, Virginia; Korecka, Magdalena; Figurski, Michal; Beckett, Laurel; Harvey, Danielle; DeCArli, Charles; Fletcher, Evan; Maillard, Pauline; Olichney, John; Carmichael, Owen; Green, Robert C; Sperling, Reisa A; Johnson, Keith A; Marshall, Gad A; Saykin, Andrew J; Foroud, Tatiana M; Shen, Li; Faber, Kelley; Kim, Sungeun; Nho, Kwangsik; Farlow, Martin R; Hake, Ann Marie; Matthews, Brandy R; Brosch, Jared R; Herring, Scott; Morris, John; Raichle, Marc; Holtzman, David; Morris, John C; Cairns, Nigel J; Franklin, Erin; Taylor-Reinwald, Lisa; Ances, Beau; Winkfield, David; Carroll, Maria; Oliver, Angela; Creech, Mary L; Mintun, Mark A; Schneider, Stacy; Kuller, Lew; Mathis, Chet; Lopez, Oscar L; Oakley, MaryAnn; Simpson, Donna M; Paul, Steven; Relkin, Norman; Chiang, Gloria; Lin, Michael; Ravdin, Lisa; Davies, Peter; Mesulam, M Marcel; Mesulam, Marek-Marsel; Rogalski, Emily; Lipowski, Kristine; Weintraub, Sandra; Bonakdarpour, Borna; Kerwin, Diana; Wu, Chuang-Kuo; Johnson, Nancy; Snyder, Peter J; Montine, Tom; Donohue, Michael; Thal, Lean; Brewer, James; Vanderswag, Helen; Fleisher, Adam; Thompson, Paul; Woo, Ellen; Silverman, Daniel H S; Teng, Edmond; Kremen, Sarah; Apostolova, Liana; Tingus, Kathleen; Lu, Po H; Bartzokis, George; Koeppe, Robert A; Ziolkowski, Jaimie; Heidebrink, Judith L; Lord, Joanne L; Foster, Norm; Albert, Marilyn; Onyike, Chiadi; D'Agostino, Daniel; Kielb, Stephanie; Quinn, Joseph; Silbert, Lisa C; Lind, Betty; Kaye, Jeffrey A; Carter, Raina; Dolen, Sara; Villanueva-Meyer, Javier; Pavlik, Valory; Pacini, Nathaniel; Lamb, Ashley; Kass, Joseph S; Doody, Rachelle S; Shibley, Victoria; Chowdhury, Munir; Rountree, Susan; Dang, Mimi; Stern, Yaakov; Honig, Lawrence S; Bell, Karen L; Yeh, Randy; Marson, Daniel; Geldmacher, David; Natelson, Marissa; Griffith, Randall; Clark, David; Brockington, John; Grossman, Hillel; Mitsis, Effie; Shah, Raj C; Lamar, Melissa; Samuels, Patricia; Sadowski, Martin; Sheikh, Mohammed O; Singleton-Garvin, Jamika; Ulysse, Anaztasia; Gaikwad, Mrunalini; Doraiswamy, P Murali; James, Olga; Borges-Neto, Salvador; Wong, Terence Z; Coleman, Edward; Smith, Charles D; Jicha, Greg; Hardy, Peter; El Khouli, Riham; Oates, Elizabeth; Conrad, Gary; Porsteinsson, Anton P; Martin, Kim; Kowalksi, Nancy; Keltz, Melanie; Goldstein, Bonnie S; Makino, Kelly M; Ismail, M Saleem; Brand, Connie; Thai, Gaby; Pierce, Aimee; Yanez, Beatriz; Sosa, Elizabeth; Witbracht, Megan; Potkin, Steven; Womack, Kyle; Mathews, Dana; Quiceno, Mary; Levey, Allan I; Lah, James J; Cellar, Janet S; Burns, Jeffrey M; Swerdlow, Russell H; Brooks, William M; van Dyck, Christopher H; Carson, Richard E; Varma, Pradeep; Chertkow, Howard; Bergman, Howard; Hosein, Chris; Turner, Raymond Scott; Johnson, Kathleen; Reynolds, Brigid; Kowall, Neil; Killiany, Ronald; Budson, Andrew E; Norbash, Alexander; Johnson, Patricia Lynn; Obisesan, Thomas O; Oyonumo, Ntekim E; Allard, Joanne; Ogunlana, Olu; Lerner, Alan; Ogrocki, Paula; Tatsuoka, Curtis; Fatica, Parianne; Johnson, Sterling; Asthana, Sanjay; Carlsson, Cynthia M; Yesavage, Jerome; Taylor, Joy L; Chao, Steven; Lane, Barton; Rosen, Allyson; Tinklenberg, Jared; Scharre, Douglas W; Kataki, Maria; Tarawneh, Rawan; Zimmerman, Earl A; Celmins, Dzintra; Hart, David; Flashman, Laura A; Seltzer, Marc; Hynes, Mary L; Santulli, Robert B; Sink, Kaycee M; Yang, Mia; Mintz, Akiva; Miller, Delwyn D; Smith, Karen Ekstam; Koleva, Hristina; Nam, Ki Won; Shim, Hyungsub; Schultz, Susan K; Smith, Amanda; Leach, Christi; Raj, Balebail Ashok; Fargher, Kristin; Reiman, Eric M; Chen, Kewei; Tariot, Pierre; Burke, Anna; Hetelle, Joel; DeMarco, Kathryn; Trncic, Nadira; Fleisher, Adam; Reeder, Stephanie; Zamrini, Edward; Belden, Christine M; Sirrel, Sherye A; Duara, Ranjan; Greig-Custo, Maria T; Rodriguez, Rosemarie; Bernick, Charles; Munic, Donna; Khachaturian, Zaven; Buckholtz, Neil; Hsiao, John; Potter, William; Fillit, Howard; Hefti, Franz; Sadowsky, Carl; Villena, Teresa; Hsiung, Ging-Yuek Robin; Mudge, Benita; Sossi, Vesna; Feldman, Howard; Assaly, Michele; Finger, Elizabeth; Pasternack, Stephen; Pavlosky, William; Rachinsky, Irina; Drost, Dick; Kertesz, Andrew; Black, Sandra; Stefanovic, Bojana; Heyn, Chrinthaka; Ott, Brian R; Tremont, Geoffrey; Daniello, Lori A; Bodge, Courtney; Salloway, Stephen; Malloy, Paul; Correia, Stephen; Lee, Athena; Pearlson, Godfrey D; Blank, Karen; Anderson, Karen; Bates, Vernice; Capote, Horacio; Rainka, Michelle; Mintzer, Jacobo; Spicer, Kenneth; Bachman, David; Finger, Elizabeth; Pasternak, Stephen; Rachinsky, Irina; Rogers, John; Kertesz, Andrew; Drost, Dick; Finger, Elizabeth; Pasternak, Stephen; Rachinsky, Irina; Rogers, John; Kertesz, Andrew; Drost, Dick; Pomara, Nunzio; Hernando, Raymundo; Sarrael, Antero; Kittur, Smita; Borrie, Michael; Lee, T-Y; Bartha, Rob; Frank, Richard; Fox, Nick; Logovinsky, Veronika; Corrillo, Maria; Sorensen, Greg
Alzheimer's disease (AD) is characterized by amyloid plaques and progressive cerebral atrophy. Here, we report FAM222A as a putative brain atrophy susceptibility gene. Our cross-phenotype association analysis of imaging genetics indicates a potential link between FAM222A and AD-related regional brain atrophy. The protein encoded by FAM222A is predominantly expressed in the CNS and is increased in brains of patients with AD and in an AD mouse model. It accumulates within amyloid deposits, physically interacts with amyloid-β (Aβ) via its N-terminal Aβ binding domain, and facilitates Aβ aggregation. Intracerebroventricular infusion or forced expression of this protein exacerbates neuroinflammation and cognitive dysfunction in an AD mouse model whereas ablation of this protein suppresses the formation of amyloid deposits, neuroinflammation and cognitive deficits in the AD mouse model. Our data support the pathological relevance of protein encoded by FAM222A in AD.
PMCID:6972869
PMID: 31964863
ISSN: 2041-1723
CID: 5134432