Articles

Brain mechanisms underlying neuropsychiatric symptoms in Alzheimer’s disease: a systematic review of symptom-general and –specific lesion patterns

Neuropsychiatric symptoms (NPSs) are common in patients with Alzheimer’s disease (AD) and are associated with accelerated cognitive impairment and earlier deaths. This review aims to explore the neural pathoge...

Authors: Yaojing Chen, Mingxi Dang and Zhanjun Zhang

“Don’t Phos Over Tau”: recent developments in clinical biomarkers and therapies targeting tau phosphorylation in Alzheimer’s disease and other tauopathies

Phosphorylation is one of the most prevalent post-translational modifications found in aggregated tau isolated from Alzheimer’s disease (AD) patient brains. In tauopathies like AD, increased phosphorylation or...

Authors: Yuxing Xia, Stefan Prokop and Benoit I. Giasson

Neuroprotection by Wld^S depends on retinal ganglion cell type and age in glaucoma

Early challenges to axonal physiology, active transport, and ultrastructure are endemic to age-related neurodegenerative disorders, including those affecting the optic nerve. Chief among these, glaucoma causes...

Authors: Michael L. Risner, Silvia Pasini, Nolan R. McGrady, Karis B. D’Alessandro, Vincent Yao, Melissa L. Cooper and David J. Calkins

Parkinson mice show functional and molecular changes in the gut long before motoric disease onset

There is increasing evidence that Parkinson’s disease (PD) might start in the gut, thus involving and compromising also the enteric nervous system (ENS). At the clinical onset of the disease the majority of do...

Authors: Manuela Gries, Anne Christmann, Steven Schulte, Maximilian Weyland, Stephanie Rommel, Monika Martin, Marko Baller, Ralph Röth, Stefanie Schmitteckert, Marcus Unger, Yang Liu, Frederik Sommer, Timo Mühlhaus, Michael Schroda, Jean-Pierre Timmermans, Isabel Pintelon…

Oligomerization of Lrrk controls actin severing and α-synuclein neurotoxicity in vivo

Mutations in LRRK2 are the most common cause of familial Parkinson’s disease and typically cause disease in the context of abnormal aggregation and deposition of α-synuclein within affected brain tissue.

Authors: Souvarish Sarkar, Farah Bardai, Abby L. Olsen, Kelly M. Lohr, Ying-Yi Zhang and Mel B. Feany

Modulating innate immune activation states impacts the efficacy of specific Aβ immunotherapy

Passive immunotherapies targeting Aβ continue to be evaluated as Alzheimer’s disease (AD) therapeutics, but there remains debate over the mechanisms by which these immunotherapies work. Besides the amount of p...

Authors: Yona Levites, Cory Funk, Xue Wang, Paramita Chakrabarty, Karen N. McFarland, Baxter Bramblett, Veronica O’Neal, Xufei Liu, Thomas Ladd, Max Robinson, Mariet Allen, Minerva M. Carrasquillo, Dennis Dickson, Pedro Cruz, Danny Ryu, Hong-Dong Li…

Genome-wide histone acetylation analysis reveals altered transcriptional regulation in the Parkinson’s disease brain

Parkinson’s disease (PD) is a complex, age-related neurodegenerative disorder of largely unknown etiology. PD is strongly associated with mitochondrial respiratory dysfunction, which can lead to epigenetic dys...

Authors: Lilah Toker, Gia T. Tran, Janani Sundaresan, Ole-Bjørn Tysnes, Guido Alves, Kristoffer Haugarvoll, Gonzalo S. Nido, Christian Dölle and Charalampos Tzoulis

A blood-based diagnostic test incorporating plasma Aβ42/40 ratio, ApoE proteotype, and age accurately identifies brain amyloid status: findings from a multi cohort validity analysis

The development of blood-based biomarker tests that are accurate and robust for Alzheimer’s disease (AD) pathology have the potential to aid clinical diagnosis and facilitate enrollment in AD drug trials. We d...

Authors: Tim West, Kristopher M. Kirmess, Matthew R. Meyer, Mary S. Holubasch, Stephanie S. Knapik, Yan Hu, John H. Contois, Erin N. Jackson, Scott E. Harpstrite, Randall J. Bateman, David M. Holtzman, Philip B. Verghese, Ilana Fogelman, Joel B. Braunstein and Kevin E. Yarasheski

Protective genes and pathways in Alzheimer’s disease: moving towards precision interventions

Alzheimer’s disease (AD) is a progressive, neurodegenerative disorder that is characterized by neurodegeneration, cognitive impairment, and an eventual inability to perform daily tasks. The etiology of Alzheim...

Authors: Mabel Seto, Rebecca L. Weiner, Logan Dumitrescu and Timothy J. Hohman

Mitochondrial complex I abnormalities is associated with tau and clinical symptoms in mild Alzheimer’s disease

Mitochondrial electron transport chain abnormalities have been reported in postmortem pathological specimens of Alzheimer’s disease (AD). However, it remains unclear how amyloid and tau are associated with mit...

Authors: Tatsuhiro Terada, Joseph Therriault, Min Su Peter Kang, Melissa Savard, Tharick Ali Pascoal, Firoza Lussier, Cecile Tissot, Yi-Ting Wang, Andrea Benedet, Takashi Matsudaira, Tomoyasu Bunai, Tomokazu Obi, Hideo Tsukada, Yasuomi Ouchi and Pedro Rosa-Neto

Beyond association: successes and challenges in linking non-coding genetic variation to functional consequences that modulate Alzheimer’s disease risk

Alzheimer’s disease (AD) is the most common type of dementia, affecting millions of people worldwide; however, no disease-modifying treatments are currently available. Genome-wide association studies (GWASs) h...

Authors: Gloriia Novikova, Shea J. Andrews, Alan E. Renton and Edoardo Marcora

Calcium-dependent cytosolic phospholipase A₂ activation is implicated in neuroinflammation and oxidative stress associated with ApoE4

Apolipoprotein E4 (APOE4) is associated with a greater response to neuroinflammation and the risk of developing late-onset Alzheimer’s disease (AD), but the mechanisms for this association are not clear. The acti...

Authors: Shaowei Wang, Boyang Li, Victoria Solomon, Alfred Fonteh, Stanley I. Rapoport, David A. Bennett, Zoe Arvanitakis, Helena C. Chui, Carol Miller, Patrick M. Sullivan, Hoau-Yan Wang and Hussein N. Yassine

AIF3 splicing switch triggers neurodegeneration

Apoptosis-inducing factor (AIF), as a mitochondrial flavoprotein, plays a fundamental role in mitochondrial bioenergetics that is critical for cell survival and also mediates caspase-independent cell death onc...

Authors: Shuiqiao Liu, Mi Zhou, Zhi Ruan, Yanan Wang, Calvin Chang, Masayuki Sasaki, Veena Rajaram, Andrew Lemoff, Kalyani Nambiar, Jennifer E. Wang, Kimmo J. Hatanpaa, Weibo Luo, Ted M. Dawson, Valina L. Dawson and Yingfei Wang

Correction to: Plaque associated microglia hyper-secrete extracellular vesicles and accelerate tau propagation in a humanized APP mouse model

An amendment to this paper has been published and can be accessed via the original article.

Authors: Kevin Clayton, Jean Christophe Delpech, Shawn Herron, Naotoshi Iwahara, Maria Ericsson, Takashi Saito, Takaomi C. Saido, Seiko Ikezu and Tsuneya Ikezu

Adiponectin-mimetic novel nonapeptide rescues aberrant neuronal metabolic-associated memory deficits in Alzheimer’s disease

Recently, we and other researchers reported that brain metabolic disorders are implicated in Alzheimer’s disease (AD), a progressive, devastating and incurable neurodegenerative disease. Hence, novel therapeut...

Authors: Tahir Ali, Shafiq Ur Rehman, Amjad Khan, Haroon Badshah, Noman Bin Abid, Min Woo Kim, Myeung Hoon Jo, Seung Soo Chung, Hyoung-gon Lee, Bart P. F. Rutten and Myeong Ok Kim

TREM2/PLCγ2 signalling in immune cells: function, structural insight, and potential therapeutic modulation

The central role of the resident innate immune cells of the brain (microglia) in neurodegeneration has become clear over the past few years largely through genome-wide association studies (GWAS), and has rapid...

Authors: Lorenza Magno, Tom D. Bunney, Emma Mead, Fredrik Svensson and Magda N. Bictash

Correction to: New approaches to symptomatic treatments for Alzheimer’s disease

An amendment to this paper has been published and can be accessed via the original article.

Authors: Jeffrey Cummings

Fred W. van Leeuwen (1949–2021)

Authors: Bert M. Verheijen and Aaron Ciechanover

The CD33 short isoform is a gain-of-function variant that enhances Aβ_1–42 phagocytosis in microglia

CD33 is genetically linked to Alzheimer’s disease (AD) susceptibility through differential expression of isoforms in microglia. The role of the human CD33 short isoform (hCD33m), preferentially encoded by an A...

Authors: Abhishek Bhattacherjee, Jaesoo Jung, Sameera Zia, Madelene Ho, Ghazaleh Eskandari-Sedighi, Chris D. St. Laurent, Kelli A. McCord, Arjun Bains, Gaurav Sidhu, Susmita Sarkar, Jason R. Plemel and Matthew S. Macauley

Plaque associated microglia hyper-secrete extracellular vesicles and accelerate tau propagation in a humanized APP mouse model

Recent studies suggest that microglia contribute to tau pathology progression in Alzheimer’s disease. Amyloid plaque accumulation transforms microglia, the primary innate immune cells in the brain, into neurod...

Authors: Kevin Clayton, Jean Christophe Delpech, Shawn Herron, Naotoshi Iwahara, Maria Ericsson, Takashi Saito, Takaomi C. Saido, Seiko Ikezu and Tsuneya Ikezu

Preclinical modeling of chronic inhibition of the Parkinson’s disease associated kinase LRRK2 reveals altered function of the endolysosomal system in vivo

The most common mutation in the Leucine-rich repeat kinase 2 gene (LRRK2), G2019S, causes familial Parkinson’s Disease (PD) and renders the encoded protein kinase hyperactive. While targeting LRRK2 activity is...

Authors: Jillian H. Kluss, Melissa Conti Mazza, Yan Li, Claudia Manzoni, Patrick A. Lewis, Mark R. Cookson and Adamantios Mamais

High dose expression of heme oxigenase-1 induces retinal degeneration through ER stress-related DDIT3

Oxidative stress is a common cause of neurodegeneration and plays a central role in retinal degenerative diseases. Heme oxygenase-1 (HMOX1) is a redox-regulated enzyme that is induced in neurodegenerative dise...

Authors: Huirong Li, Bo Liu, Lili Lian, Jiajia Zhou, Shengjin Xiang, Yifan Zhai, Yu Chen, Xiaoyin Ma, Wencan Wu and Ling Hou

Cholesterol alters mitophagy by impairing optineurin recruitment and lysosomal clearance in Alzheimer’s disease

Emerging evidence indicates that impaired mitophagy-mediated clearance of defective mitochondria is a critical event in Alzheimer’s disease (AD) pathogenesis. Amyloid-beta (Aβ) metabolism and the microtubule-a...

Authors: Vicente Roca-Agujetas, Elisabet Barbero-Camps, Cristina de Dios, Petar Podlesniy, Xenia Abadin, Albert Morales, Montserrat Marí, Ramon Trullàs and Anna Colell

Enhancing GABAergic signaling ameliorates aberrant gamma oscillations of olfactory bulb in AD mouse models

Before the deposition of amyloid-beta plaques and the onset of learning memory deficits, patients with Alzheimer’s disease (AD) experience olfactory dysfunction, typified by a reduced ability to detect, discri...

Authors: Ming Chen, Yunan Chen, Qingwei Huo, Lei Wang, Shuyi Tan, Afzal Misrani, Jinxiang Jiang, Jian Chen, Shiyuan Chen, Jiawei Zhang, Sidra Tabassum, Jichen Wang, Xi Chen, Cheng Long and Li Yang

Altered network properties in C9ORF72 repeat expansion cortical neurons are due to synaptic dysfunction

Physiological disturbances in cortical network excitability and plasticity are established and widespread in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) patients, including those harb...

Authors: Emma M. Perkins, Karen Burr, Poulomi Banerjee, Arpan R. Mehta, Owen Dando, Bhuvaneish T. Selvaraj, Daumante Suminaite, Jyoti Nanda, Christopher M. Henstridge, Thomas H. Gillingwater, Giles E. Hardingham, David J. A. Wyllie, Siddharthan Chandran and Matthew R. Livesey

Dominant mutations in MIEF1 affect mitochondrial dynamics and cause a singular late onset optic neuropathy

Inherited optic neuropathies are the most common mitochondrial diseases, leading to neurodegeneration involving the irreversible loss of retinal ganglion cells, optic nerve degeneration and central visual loss...

Authors: Majida Charif, Yvette C. Wong, Soojin Kim, Agnès Guichet, Catherine Vignal, Xavier Zanlonghi, Philippe Bensaid, Vincent Procaccio, Dominique Bonneau, Patrizia Amati-Bonneau, Pascal Reynier, Dimitri Krainc and Guy Lenaers

Prion protein oligomers cause neuronal cytoskeletal damage in rapidly progressive Alzheimer’s disease

High-density oligomers of the prion protein (HDPs) have previously been identified in brain tissues of patients with rapidly progressive Alzheimer’s disease (rpAD). The current investigation aims at identifyin...

Authors: Mohsin Shafiq, Saima Zafar, Neelam Younas, Aneeqa Noor, Berta Puig, Hermann Clemens Altmeppen, Matthias Schmitz, Jakob Matschke, Isidre Ferrer, Markus Glatzel and Inga Zerr

Moving fluid biomarkers for Alzheimer’s disease from research tools to routine clinical diagnostics

Four fluid-based biomarkers have been developed into diagnostic tests for Alzheimer’s disease (AD) pathology: the ratio of 42 to 40 amino acid-long amyloid β, a marker of plaque pathology; total-tau and phosph...

Authors: Henrik Zetterberg and Kaj Blennow

Deletion of Socs3 in LysM⁺ cells and Cx3cr1 resulted in age-dependent development of retinal microgliopathy

We generated a mouse model of primary microglial dysfunction by deleting two negative immune regulatory genes, Cx3cr1 and Socs3 (in LysM⁺ cells). This study aimed to understand how primary microglial dysfunction ...

Authors: Xuan Du, Rosana Penalva, Karis Little, Adrien Kissenpfennig, Mei Chen and Heping Xu

Remodeling Alzheimer-amyloidosis models by seeding

Alzheimer’s disease (AD) is among the most prevalent neurodegenerative diseases, with brain pathology defined by extracellular amyloid beta deposits and intracellular tau aggregates. To aid in research efforts...

Authors: Brittany S. Ulm, David R. Borchelt and Brenda D. Moore

Increased serum QUIN/KYNA is a reliable biomarker of post-stroke cognitive decline

Strokes are becoming less severe due to increased numbers of intensive care units and improved treatments. As patients survive longer, post-stroke cognitive impairment (PSCI) has become a major health public i...

Authors: Adrien Cogo, Gabrielle Mangin, Benjamin Maïer, Jacques Callebert, Mikael Mazighi, Hughes Chabriat, Jean-Marie Launay, Gilles Huberfeld and Nathalie Kubis

Relationships of gut microbiota, short-chain fatty acids, inflammation, and the gut barrier in Parkinson’s disease

Previous studies have reported that gut microbiota, permeability, short-chain fatty acids (SCFAs), and inflammation are altered in Parkinson’s disease (PD), but how these factors are linked and how they contri...

Authors: Velma T. E. Aho, Madelyn C. Houser, Pedro A. B. Pereira, Jianjun Chang, Knut Rudi, Lars Paulin, Vicki Hertzberg, Petri Auvinen, Malú G. Tansey and Filip Scheperjans

Clusterin secreted from astrocyte promotes excitatory synaptic transmission and ameliorates Alzheimer’s disease neuropathology

Genome-wide association studies have established clusterin (CLU) as a genetic modifier for late-onset Alzheimer’s disease (AD). Both protective and risk alleles have been identified which may be associated wit...

Authors: Fading Chen, Dan B. Swartzlander, Anamitra Ghosh, John D. Fryer, Baiping Wang and Hui Zheng

Comprehensive metabolic profiling of Parkinson’s disease by liquid chromatography-mass spectrometry

Parkinson’s disease (PD) is a prevalent neurological disease in the elderly with increasing morbidity and mortality. Despite enormous efforts, rapid and accurate diagnosis of PD is still compromised. Metabolom...

Authors: Yaping Shao, Tianbai Li, Zheyi Liu, Xiaolin Wang, Xiaojiao Xu, Song Li, Guowang Xu and Weidong Le

Methods to investigate intrathecal adaptive immunity in neurodegeneration

Cerebrospinal fluid (CSF) provides basic mechanical and immunological protection to the brain. Historically, analysis of CSF has focused on protein changes, yet recent studies have shed light on cellular alter...

Authors: Hamilton Oh, Olivia Leventhal, Divya Channappa, Victor W. Henderson, Tony Wyss-Coray, Benoit Lehallier and David Gate

New approaches to symptomatic treatments for Alzheimer’s disease

Successful development of agents that improve cognition and behavior in Alzheimer’s disease (AD) is critical to improving the lives of patients manifesting the symptoms of this progressive disorder.

Authors: Jeffrey Cummings

Induction of autophagy mitigates TDP-43 pathology and translational repression of neurofilament mRNAs in mouse models of ALS/FTD

TDP-43 proteinopathy is a pathological hallmark of many neurodegenerative diseases including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). So far, there is no therapy available for the...

Authors: Sunny Kumar, Daniel Phaneuf, Pierre Cordeau Jr., Hejer Boutej, Jasna Kriz and Jean-Pierre Julien

Cell-autonomous role of Presenilin in age-dependent survival of cortical interneurons

Mutations in the PSEN1 and PSEN2 genes are the major cause of familial Alzheimer’s disease. Previous studies demonstrated that Presenilin (PS), the catalytic subunit of γ-secretase, is required for survival of ex...

Authors: Jongkyun Kang and Jie Shen

Astrocyte-derived clusterin suppresses amyloid formation in vivo

Accumulation of amyloid-β (Aβ) peptide in the brain is a pathological hallmark of Alzheimer’s disease (AD). The clusterin (CLU) gene confers a risk for AD and CLU is highly upregulated in AD patients, with the co...

Authors: Aleksandra M. Wojtas, Jonathon P. Sens, Silvia S. Kang, Kelsey E. Baker, Taylor J. Berry, Aishe Kurti, Lillian Daughrity, Karen R. Jansen-West, Dennis W. Dickson, Leonard Petrucelli, Guojun Bu, Chia-Chen Liu and John D. Fryer

Regional binding of tau and amyloid PET tracers in Down syndrome autopsy brain tissue

Tau pathology is a major age-related event in Down syndrome with Alzheimer’s disease (DS-AD). Although recently, several different Tau PET tracers have been developed as biomarkers for AD, these tracers showed...

Authors: L. Lemoine, A. Ledreux, E. J. Mufson, S. E. Perez, G. Simic, E. Doran, I. Lott, S. Carroll, K. Bharani, S. Thomas, A. Gilmore, E. D. Hamlett, A. Nordberg and A. C. Granholm

An in vitro bioengineered model of the human arterial neurovascular unit to study neurodegenerative diseases

The neurovascular unit (NVU) – the interaction between the neurons and the cerebrovasculature – is increasingly important to interrogate through human-based experimental models. Although advanced models of cer...

Authors: Jerome Robert, Nicholas L. Weilinger, Li-Ping Cao, Stefano Cataldi, Emily B. Button, Sophie Stukas, Emma M. Martin, Philip Seibler, Megan Gilmour, Tara M. Caffrey, Elyn M. Rowe, Jianjia Fan, Brian MacVicar, Matthew J. Farrer and Cheryl L. Wellington

Activity of Alzheimer’s γ-secretase is linked to changes of interferon-induced transmembrane proteins (IFITM) in innate immunity

The activity of γ-secretase is critical to the pathogenesis of Alzheimer’s disease (AD). How its activity is regulated is intriguing and highly important for any AD therapy that focuses on reduction of toxic a...

Authors: Annie Y. Yao and Riqiang Yan

A novel systems biology approach to evaluate mouse models of late-onset Alzheimer’s disease

Late-onset Alzheimer’s disease (LOAD) is the most common form of dementia worldwide. To date, animal models of Alzheimer’s have focused on rare familial mutations, due to a lack of frank neuropathology from mo...

Authors: Christoph Preuss, Ravi Pandey, Erin Piazza, Alexander Fine, Asli Uyar, Thanneer Perumal, Dylan Garceau, Kevin P. Kotredes, Harriet Williams, Lara M. Mangravite, Bruce T. Lamb, Adrian L. Oblak, Gareth R. Howell, Michael Sasner, Benjamin A. Logsdon and Gregory W. Carter

Diabetic phenotype in mouse and humans reduces the number of microglia around β-amyloid plaques

Alzheimer’s disease (AD) is the most common neurodegenerative disease and type 2 diabetes (T2D) plays an important role in conferring the risk for AD. Although AD and T2D share common features, the common mole...

Authors: Teemu Natunen, Henna Martiskainen, Mikael Marttinen, Sami Gabbouj, Hennariikka Koivisto, Susanna Kemppainen, Satu Kaipainen, Mari Takalo, Helena Svobodová, Luukas Leppänen, Benjam Kemiläinen, Simo Ryhänen, Teemu Kuulasmaa, Eija Rahunen, Sisko Juutinen, Petra Mäkinen…

Tauopathy-associated tau modifications selectively impact neurodegeneration and mitophagy in a novel C. elegans single-copy transgenic model

A defining pathological hallmark of the progressive neurodegenerative disorder Alzheimer’s disease (AD) is the accumulation of misfolded tau with abnormal post-translational modifications (PTMs). These include...

Authors: Sanjib Guha, Sarah Fischer, Gail V. W. Johnson and Keith Nehrke

Conformation-selective tau monoclonal antibodies inhibit tau pathology in primary neurons and a mouse model of Alzheimer’s disease

The spread of tau pathology in Alzheimer’s disease (AD) is mediated by cell-to-cell transmission of pathological tau seeds released from neurons that, upon internalization by recipient neurons, template the mi...

Authors: Garrett S. Gibbons, Soo-Jung Kim, Qihui Wu, Dawn M. Riddle, Susan N. Leight, Lakshmi Changolkar, Hong Xu, Emily S. Meymand, Mia O’Reilly, Bin Zhang, Kurt R. Brunden, John Q. Trojanowski and Virginia M. Y. Lee

APOE2: protective mechanism and therapeutic implications for Alzheimer’s disease

Investigations of apolipoprotein E (APOE) gene, the major genetic risk modifier for Alzheimer’s disease (AD), have yielded significant insights into the pathogenic mechanism. Among the three common coding variant...

Authors: Zonghua Li, Francis Shue, Na Zhao, Mitsuru Shinohara and Guojun Bu

Trem2 Y38C mutation and loss of Trem2 impairs neuronal synapses in adult mice

Triggering receptor expressed on myeloid cells 2 (TREM2) is expressed in the brain exclusively on microglia and genetic variants are linked to neurodegenerative diseases including Alzheimer’s disease (AD), fro...

Authors: Vaishnavi S. Jadhav, Peter B. C. Lin, Taylor Pennington, Gonzalo Viana Di Prisco, Asha Jacob Jannu, Guixiang Xu, Miguel Moutinho, Jie Zhang, Brady K. Atwood, Shweta S. Puntambekar, Stephanie J. Bissel, Adrian L. Oblak, Gary E. Landreth and Bruce T. Lamb

Aging-relevant human basal forebrain cholinergic neurons as a cell model for Alzheimer’s disease

Alzheimer’s disease (AD) is an adult-onset mental disorder with aging as a major risk factor. Early and progressive degeneration of basal forebrain cholinergic neurons (BFCNs) contributes substantially to cogn...

Authors: Shuaipeng Ma, Tong Zang, Meng-Lu Liu and Chun-Li Zhang

Modeling the β-secretase cleavage site and humanizing amyloid-beta precursor protein in rat and mouse to study Alzheimer’s disease

Three amino acid differences between rodent and human APP affect medically important features, including β-secretase cleavage of APP and Aβ peptide aggregation (De Strooper et al., EMBO J 14:4932-38, 1995; Uen...

Authors: Lutgarde Serneels, Dries T’Syen, Laura Perez-Benito, Tom Theys, Matthew G. Holt and Bart De Strooper