Microinfarcts are prevalent but tiny ischemic lesions that may contribute to vascular cognitive impairment and dementia (VCID)(Fig. 1A and B).1 They are defined as areas of tissue infarction, often with gliosis and/or cavitation, visible only by examination of the autopsied brain at a microscopic level.2, 3 Numerous autopsy studies have now shown that a greater microinfarct burden is correlated with increased likelihood of cognitive impairment.2, 3 Cerebral microinfarcts are observed post-mortem in the brains of approximately 43% of patients with Alzheimer’s disease, 62% of patients with vascular dementia, and 24% of non-demented elderly subjects.4. However, reported microinfarct numbers are a significant underestimation of total burden, as only a small portion of the brain is examined at routine autopsy.1 Indeed, they can number in the hundreds to thousands within a single brain. Microinfarcts can arise from a variety of etiologies, including cerebral small vessel disease, large vessel disease, cerebral hypoperfusion, and cardiac disease, but their role in the pathogenesis of VCID remains poorly understood.
Degeneration of locus coeruleus (LC) is an underappreciated hallmark of Alzheimer's disease (AD). The LC is the main source of norepinephrine (NE) in the forebrain, and its degeneration is highly correlated with cognitive impairment and amyloid-beta (Aβ) and tangle pathology. Hyperphosphorylated tau in the LC is among the first detectable AD-like neuropathology in the brain, and while the LC/NE system impacts multiple aspects of AD (e.g., cognition, neuropathology, and neuroinflammation), the functional consequences of hyperphosphorylated tau accrual on LC neurons are not known. Recent evidence suggests that LC neurons accumulate aberrant tau species for decades before frank LC cell body degeneration occurs in AD, suggesting that a therapeutic window exists. In this review, we combine the literature on how pathogenic tau affects forebrain neurons with the known properties and degeneration patterns of LC neurons to synthesize hypotheses on hyperphosphorylated tau-induced dysfunction of LC neurons and the prion-like spread of pretangle tau from the LC to the forebrain. We also propose novel experiments using both in vitro and in vivo models to address the many questions surrounding the impact of hyperphosphorylated tau on LC neurons in AD and its role in disease progression.
The misfolding and aggregation of the Aβ peptide - a fundamental event in the pathogenesis of Alzheimer's disease - can be instigated in the brains of experimental animals by the intracranial infusion of brain extracts that are rich in aggregated Aβ. Recent experiments have found that the peripheral (intraperitoneal) injection of Aβ seeds induces Aβ deposition in the brains of APP-transgenic mice, largely in the form of cerebral amyloid angiopathy. Macrophage-type cells normally are involved in pathogen neutralization and antigen presentation, but under some circumstances, circulating monocytes have been found to act as vectors for the transport of pathogenic agents such as viruses and prions. The present study assessed the ability of peripheral monocytes to transport Aβ aggregates from the peritoneal cavity to the brain. Our initial experiments showed that intravenously delivered macrophages that had previously ingested fluorescent nanobeads as tracers migrate primarily to peripheral organs such as spleen and liver, but that a small number also reach the brain parenchyma. We next injected CD45.1-expressing monocytes from donor mice intravenously into CD45.2-expressing host mice; after 24 h, analysis by fluorescence-activated cell sorting (FACS) and histology confirmed that some CD45.1 monocytes enter the brain, particularly in the superficial cortex and around blood vessels. When the donor monocytes are first exposed to Aβ-rich brain extracts from human AD cases, a subset of intravenously delivered Aβ-containing cells migrate to the brain. These experiments indicate that, in mouse models, circulating monocytes are potential vectors by which exogenously delivered, aggregated Aβ travels from periphery to brain, and more generally support the hypothesis that macrophage-type cells can participate in the dissemination of proteopathic seeds.
How do neurons adapt their endolysosomal system to address the particular challenge of membrane transport across their elaborate cellular landscape and to maintain proteostasis for the lifetime of the organism? Here we review recent findings that address this central question. We discuss the cellular and molecular mechanisms of endolysosomal trafficking and the autophagy pathway in neurons, as well as their role in neuronal development and degeneration. These studies highlight the importance of understanding the basic cell biology of endolysosomal trafficking and autophagy and their roles in the maintenance of proteostasis within the context of neurons, which will be critical for developing effective therapies for various neurodevelopmental and neurodegenerative disorders.
OBJECTIVES: To assess the effect of modulation of the renin-angiotensin system (RAS) on conversion to Alzheimer's disease (AD) and cognitive decline in people with mild cognitive impairment (MCI) and the effect of the permeability of the blood-brain barrier (BBB) and race on the potential relationship between the RAS and AD.
DESIGN: Analysis of data from AD centers funded by the National Alzheimer's Coordinating Center, National Institute on Aging.
SETTING: Alzheimer's Disease Centers.
PARTICIPANTS: Individuals receiving antihypertensive medications who had MCI at baseline and had cognitive assessments on at least two follow-up visits (N = 784; mean age 75 l 48/% male).
MEASUREMENTS: Conversion to AD and cognitive and functional decline.
RESULTS: Four hundred eighty-eight participants were receiving RAS-acting antihypertensive medications. RAS-acting medication users were less likely to convert to AD (33% vs 40%; P =.04) and had slower decline on the Clinical Dementia Rating Sum of Boxes (CDR-SOB, P =.005) and Digit Span Forward (P =.02) than nonusers. BBB-crossing RAS-acting medications were associated with slower cognitive decline on the CDR-SOB, (P =.009), the Mini-Mental State Examination (MMSE), (P =.001), and the Boston Naming test (P =.002). RAS-acting medications were associated with cognitive benefits more in African Americans than in Caucasians (MMSE, P =.05; category fluency, P =.04; Digit Span Backward, P =.03).
CONCLUSION: RAS-acting medication users were less likely to convert to AD. BBB permeability may produce additional cognitive benefit, and African Americans may benefit more from RAS modulation than Caucasians. Results highlight the need for trials investigating RAS modulation during prodromal disease stages.
by
Andrew T. McKenzie;
Sarah Moyon;
Minghui Wang;
Igor Katsyv;
Won-Min Song;
Xianxiao Zhou;
Eric B Dammer;
Duc M. Duong;
Joshua Aaker;
Yongzhong Zhao;
Noam Beckmann;
Pei Wang;
Jun Zhu;
James J Lah;
Nicholas Seyfried;
Allan I Levey;
Pavel Katsel;
Vahram Haroutunian;
Eric E. Schadt;
Brian Popko;
Patrizia Casaccia;
Bin Zhang
Background: Oligodendrocytes (OLs) and myelin are critical for normal brain function and have been implicated in neurodegeneration. Several lines of evidence including neuroimaging and neuropathological data suggest that Alzheimer's disease (AD) may be associated with dysmyelination and a breakdown of OL-axon communication.
Methods: In order to understand this phenomenon on a molecular level, we systematically interrogated OL-enriched gene networks constructed from large-scale genomic, transcriptomic and proteomic data obtained from human AD postmortem brain samples. We then validated these networks using gene expression datasets generated from mice with ablation of major gene expression nodes identified in our AD-dysregulated networks.
Results: The robust OL gene coexpression networks that we identified were highly enriched for genes associated with AD risk variants, such as BIN1 and demonstrated strong dysregulation in AD. We further corroborated the structure of the corresponding gene causal networks using datasets generated from the brain of mice with ablation of key network drivers, such as UGT8, CNP and PLP1, which were identified from human AD brain data. Further, we found that mice with genetic ablations of Cnp mimicked aspects of myelin and mitochondrial gene expression dysregulation seen in brain samples from patients with AD, including decreased protein expression of BIN1 and GOT2.
Conclusions: This study provides a molecular blueprint of the dysregulation of gene expression networks of OL in AD and identifies key OL- and myelination-related genes and networks that are highly associated with AD.
During the last two decades, a wealth of animal and human studies has implicated inflammation-derived oxidative stress and cytokine-dependent neurotoxicity in the progressive degeneration of the dopaminergic nigrostriatal pathway, the hallmark of Parkinson's disease (PD). In this review, we discuss the various hypotheses regarding the role of microglia and other immune cells in PD pathogenesis and progression, the inflammatory mechanisms implicated in disease progression from pre-clinical and clinical studies, the recent evidence that systemic inflammation can trigger microglia activation in PD-relevant central nervous system regions, the synergism between gene products linked to parkinsonian phenotypes (α-synuclein, parkin, Nurr1, and regulator of G-protein signaling-10) and neuroinflammation in promoting neurodegeneration of the nigrostriatal pathway, and the latest update on meta-analysis of epidemiological studies on the risk-lowering effects of anti-inflammatory drug regimens.
by
Alvaro Alonso;
David S. Knopman;
Rebecca F. Gottesman;
Elsayad Z. Soliman;
Amit Shah;
Wesley T. O'Neal;
Faye L. Norby;
Thomas H. Mosley;
Lin Y. Chen
BACKGROUND: Atrial fibrillation (AF) has been associated with faster cognitive decline and increased dementia risk. Factors associated with dementia in patients with AF have been seldom studied. METHODS AND RESULTS: We studied 6432 individuals from the ARIC-NCS (Atherosclerosis Risk in Communities Neurocognitive Study). In 2011 to 2013, participants underwent a physical exam, echocardiography, detailed cognitive assessments, and a subset, brain magnetic resonance imaging. Dementia and mild cognitive impairment (MCI), as well as etiology of MCI/dementia, Alzheimer's disease-related or vascular, were adjudicated by an expert panel. AF was defined by study ECGs and past hospitalizations. We used logistic regression to estimate odds ratios and 95% CI of MCI/dementia by AF status and to assess cross-sectional correlates of MCI/dementia in patients with AF. Among 6432 participants, 611 (9.5%) had prevalent AF. AF was associated with increased odds of dementia and MCI (odds ratio, 95% CI, 2.25, 1.64-3.10, and 1.28, 1.04-1.56, respectively). Prevalence of Alzheimer's disease-related MCI/dementia and vascular MCI/dementia were higher in participants with AF than without AF (odds ratio, 95% CI, 1.29, 1.04-1.61, and 1.50, 0.99-2.25, respectively). In multivariable analyses, older age, lower body mass index, diabetes mellitus, stroke, and APOE genotype were associated with dementia prevalence in participants with AF. In models evaluating MCI/dementia subtypes, diabetes mellitus was associated with Alzheimer's disease-related MCI/dementia, whereas male sex and stroke were risk factors for vascular MCI/dementia. CONCLUSIONS: In a large, community-based study, AF was associated with higher prevalence of MCI and dementia. Controlling cardiometabolic risk factors is a potential target for prevention of adverse cognitive outcomes in AF patients.
Clinical and animal model studies have implicated inflammation and peripheral immune cell responses in the pathophysiology of Alzheimer's disease (AD). Peripheral immune cells including T cells circulate in the cerebrospinal fluid (CSF) of healthy adults and are found in the brains of AD patients and AD rodent models. Blocking entry of peripheral macrophages into the CNS was reported to increase amyloid burden in an AD mouse model. To assess inflammation in the 5xFAD (Tg) mouse model, we first quantified central and immune cell profiles in the deep cervical lymph nodes and spleen. In the brains of Tg mice, activated (MHCII+, CD45high, and Ly6Chigh) myeloid-derived CD11b+immune cells are decreased while CD3+T cells are increased as a function of age relative to non-Tg mice. These immunological changes along with evidence of increased mRNA levels for several cytokines suggest that immune regulation and trafficking patterns are altered in Tg mice. Levels of soluble Tumor Necrosis Factor (sTNF) modulate blood-brain barrier (BBB) permeability and are increased in CSF and brain parenchyma post-mortem in AD subjects and Tg mice. We report here that in vivo peripheral administration of XPro1595, a novel biologic that sequesters sTNF into inactive heterotrimers, reduced the age-dependent increase in activated immune cells in Tg mice, while decreasing the overall number of CD4+T cells. In addition, XPro1595 treatment in vivo rescued impaired long-term potentiation (LTP) measured in brain slices in association with decreased Aβ plaques in the subiculum. Selective targeting of sTNF may modulate brain immune cell infiltration, and prevent or delay neuronal dysfunction in AD. Significance statement Immune cells and cytokines perform specialized functions inside and outside the brain to maintain optimal brain health; but the extent to which their activities change in response to neuronal dysfunction and degeneration is not well understood. Our findings indicate that neutralization of sTNF reduced the age-dependent increase in activated immune cells in Tg mice, while decreasing the overall number of CD4+T cells. In addition, impaired long-term potentiation (LTP) was rescued by XPro1595 in association with decreased hippocampal Aβ plaques. Selective targeting of sTNF holds translational potential to modulate brain immune cell infiltration, dampen neuroinflammation, and prevent or delay neuronal dysfunction in AD.
In the embryonic and adult brain, neural stem cells proliferate and give rise to neurons and glia through highly regulated processes. Epigenetic mechanisms-including DNA and histone modifications, as well as regulation by non-coding RNAs-have pivotal roles in different stages of neurogenesis. Aberrant epigenetic regulation also contributes to the pathogenesis of various brain disorders. Here, we review recent advances in our understanding of epigenetic regulation in neurogenesis and its dysregulation in brain disorders, including discussion of newly identified DNA cytosine modifications. We also briefly cover the emerging field of epitranscriptomics, which involves modifications of mRNAs and long non-coding RNAs.