Vascular Dysfunction in Alzheimer’s Disease: A Prelude to the Pathological Process or a Consequence of It?

Alzheimer’s disease (AD) is the most prevalent form of dementia. Despite decades of research following several theoretical and clinical lines, all existing treatments for the disorder are purely symptomatic. AD research has traditionally been focused on neuronal and glial dysfunction. Although there is a wealth of evidence pointing to a significant vascular component in the disease, this angle has been relatively poorly explored. In this review, we consider the various aspects of vascular dysfunction in AD, which has a significant impact on brain metabolism and homeostasis and the clearance of β-amyloid and other toxic metabolites. This may potentially precede the onset of the hallmark pathophysiological and cognitive symptoms of the disease. Pathological changes in vessel haemodynamics, angiogenesis, vascular cell function, vascular coverage, blood-brain barrier permeability and immune cell migration may be related to amyloid toxicity, oxidative stress and apolipoprotein E (APOE) genotype. These vascular deficits may in turn contribute to parenchymal amyloid deposition, neurotoxicity, glial activation and metabolic dysfunction in multiple cell types. A vicious feedback cycle ensues, with progressively worsening neuronal and vascular pathology through the course of the disease. Thus, a better appreciation for the importance of vascular dysfunction in AD may open new avenues for research and therapy.

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Single-cell transcriptomic analysis elucidates APOE genotype specific changes across cell types in two brain regions in Alzheimer’s disease

10.21203/rs.3.rs-291648/v1 ◽

2021 ◽

Author(s):

Stella Belonwu ◽

Yaqiao Li ◽

Daniel Bunis ◽

Arjun Arkal Rao ◽

Caroline Warly Solsberg ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Single Cell ◽

Molecular Mechanisms ◽

Apoe Genotype ◽

Cell Types ◽

Brain Regions ◽

Single Cell Level ◽

Cell Level ◽

Single Nucleus

Abstract Alzheimer’s Disease (AD) is a complex neurodegenerative disease that gravely affects patients and imposes an immense burden on caregivers. Apolipoprotein E4 (APOE4) has been identified as the most common genetic risk factor for AD, yet the molecular mechanisms connecting APOE4 to AD are not well understood. Past transcriptomic analyses in AD have revealed APOE genotype-specific transcriptomic differences; however, these differences have not been explored at a single-cell level. Here, we leverage the first two single-nucleus RNA sequencing AD datasets from human brain samples, including nearly 55,000 cells from the prefrontal and entorhinal cortices. We observed more global transcriptomic changes in APOE4 positive AD cells and identified differences across APOE genotypes primarily in glial cell types. Our findings highlight the differential transcriptomic perturbations of APOE isoforms at a single-cell level in AD pathogenesis and have implications for precision medicine development in the diagnosis and treatment of AD.

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Paired Immunoglobulin-like Type 2 Receptor Alpha G78R variant alters ligand binding and confers protection to Alzheimer’s disease

10.1101/325936 ◽

2018 ◽

Author(s):

Nisha Rathore ◽

Sree Ranjani Ramani ◽

Homer Pantua ◽

Jian Payandeh ◽

Tushar Bhangale ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Immune Cell ◽

Disease Risk ◽

Missense Variant ◽

Cell Types ◽

Glycoprotein B ◽

Receptor Alpha ◽

Hsv 1

AbstractPaired Immunoglobulin-like Type 2 Receptor Alpha (PILRA) is a cell surface inhibitory receptor that recognizes specific O-glycosylated proteins and is expressed on various innate immune cell types including microglia. We show here that a common missense variant (G78R, rs1859788) of PILRA is the likely causal allele for the confirmed Alzheimer’s disease risk locus at 7q21 (rs1476679). The G78R variant alters the interaction of residues essential for sialic acid engagement, resulting in >50% reduced binding for several PILRA ligands including a novel ligand, complement component 4A, and herpes simplex virus 1 (HSV-1) glycoprotein B. PILRA is an entry receptor for HSV-1 via glycoprotein B, and macrophages derived from R78 homozygous donors showed significantly decreased levels of HSV-1 infection at several multiplicities of infection compared to homozygous G78 macrophages. We propose that PILRA G78R protects individuals from Alzheimer’s disease risk via reduced inhibitory signaling in microglia and reduced microglial infection during HSV-1 recurrence.

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Alzheimer’s disease Phospholipase C-gamma-2 (PLCG2) protective variant is a functional hypermorph

10.1101/409706 ◽

2018 ◽

Cited By ~ 2

Author(s):

Lorenza Magno ◽

Christian B Lessard ◽

Marta Martins ◽

Pedro Cruz ◽

Matilda Katan ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Phospholipase C ◽

Cell Function ◽

Immune Cell ◽

Late Onset ◽

Association Studies ◽

Enzyme Function ◽

Genome Wide Association Studies ◽

Phospholipase C Gamma

ABSTRACTRecent Genome Wide Association Studies (GWAS) have identified novel rare coding variants in immune genes associated with late onset AD (LOAD). Amongst these, a polymorphism in Phospholipase C-gamma 2 (PLCG2) P522R, has been reported to be protective against LOAD. PLC enzymes are key elements in signal transmission networks and are potentially druggable targets. PLCG2 is highly expressed in the hematopoietic system. Hypermorphic mutations in PLCG2 in humans have been reported to cause autoinflammation and immune disorders, suggesting a key role for this enzyme in the regulation of immune cell function.We confirmed that PLCG2 expression is restricted primarily to microglia in both the healthy and AD brain. Functional analysis of the P522R variant in heterologous systems demonstrated a small hypermorphic effect of the mutation on enzyme function. PLCγ2 is therefore a potential target for modulating microglia function in AD, and a small molecule drug that weakly activates PLCγ2 may be one potential therapeutic approach.SUMMARYThe PLCG2 P522R variant is protective against Alzheimer’s disease (AD). We show that PLCG2 is expressed in CNS-resident myeloid cells, and the P522R polymorphism weakly activates enzyme function. These data suggest that activation of PLCG2 and not inhibition could be therapeutically beneficial in AD.

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A Leaky Blood–Brain Barrier to Fibrinogen Contributes to Oxidative Damage in Alzheimer’s Disease

Antioxidants ◽

10.3390/antiox11010102 ◽

2021 ◽

Vol 11 (1) ◽

pp. 102

Author(s):

James G. McLarnon

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Blood Brain Barrier ◽

Immune Cell ◽

Neurovascular Unit ◽

Amyloid Β ◽

Brain Barrier ◽

Vascular Pathology ◽

Immune Reactivity ◽

Blood Brain

The intactness of blood–brain barrier (BBB) is compromised in Alzheimer’s disease (AD). Importantly, evidence suggests that the perturbation and abnormalities appearing in BBB can manifest early in the progression of the disease. The disruption of BBB allows extravasation of the plasma protein, fibrinogen, to enter brain parenchyma, eliciting immune reactivity and response. The presence of amyloid-β (Aβ) peptide leads to the formation of abnormal aggregates of fibrin resistant to degradation. Furthermore, Aβ deposits act on the contact system of blood coagulation, altering levels of thrombin, fibrin clots and neuroinflammation. The neurovascular unit (NVU) comprises an ensemble of brain cells which interact with infiltrating fibrinogen. In particular, interaction of resident immune cell microglia with fibrinogen, fibrin and Aβ results in the production of reactive oxygen species (ROS), a neurotoxic effector in AD brain. Overall, fibrinogen infiltration through a leaky BBB in AD animal models and in human AD tissue is associated with manifold abnormalities including persistent fibrin aggregation and clots, microglial-mediated production of ROS and diminished viability of neurons and synaptic connectivity. An objective of this review is to better understand how processes associated with BBB leakiness to fibrinogen link vascular pathology with neuronal and synaptic damage in AD.

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A common haplotype lowers PU.1 expression in myeloid cells and delays onset of Alzheimer’s disease

10.1101/110957 ◽

2017 ◽

Cited By ~ 1

Author(s):

Kuan-lin Huang ◽

Edoardo Marcora ◽

Anna A Pimenova ◽

Antonio F Di Narzo ◽

Manav Kapoor ◽

...

Keyword(s):

Gene Expression ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cell Function ◽

Age At Onset ◽

Myeloid Cell ◽

Cell Types ◽

A Genome ◽

Monocytes And Macrophages ◽

And Function

AbstractA genome-wide survival analysis of 14,406 Alzheimer’s disease (AD) cases and 25,849 controls identified eight previously reported AD risk loci and fourteen novel loci associated with age at onset. LD score regression of 220 cell types implicated regulation of myeloid gene expression in AD risk. In particular, the minor allele of rs1057233 (G), within the previously reported CELF1 AD risk locus, showed association with delayed AD onset and lower expression of SPI1 in monocytes and macrophages. SPI1 encodes PU.1, a transcription factor critical for myeloid cell development and function. AD heritability is enriched within the PU.1 cistrome, implicating a myeloid PU.1 target gene network in AD. Finally, experimentally altered PU.1 levels affect the expression of mouse orthologs of many AD risk genes and the phagocytic activity of mouse microglial cells. Our results suggest that lower SPI1 expression reduces AD risk by regulating myeloid gene expression and cell function.

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Role of Neuron and Glia in Alzheimer’s Disease and Associated Vascular Dysfunction

Frontiers in Aging Neuroscience ◽

10.3389/fnagi.2021.653334 ◽

2021 ◽

Vol 13 ◽

Author(s):

Sanghamitra Bandyopadhyay

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Large Scale ◽

Vascular Dysfunction ◽

Critical Role ◽

Amyloid Β ◽

Neuronal Loss ◽

Cell Types ◽

Cellular Interactions

Amyloidogenicity and vascular dysfunction are the key players in the pathogenesis of Alzheimer’s disease (AD), involving dysregulated cellular interactions. An intricate balance between neurons, astrocytes, microglia, oligodendrocytes and vascular cells sustains the normal neuronal circuits. Conversely, cerebrovascular diseases overlap neuropathologically with AD, and glial dyshomeostasis promotes AD-associated neurodegenerative cascade. While pathological hallmarks of AD primarily include amyloid-β (Aβ) plaques and neurofibrillary tangles, microvascular disorders, altered cerebral blood flow (CBF), and blood-brain barrier (BBB) permeability induce neuronal loss and synaptic atrophy. Accordingly, microglia-mediated inflammation and astrogliosis disrupt the homeostasis of the neuro-vascular unit and stimulate infiltration of circulating leukocytes into the brain. Large-scale genetic and epidemiological studies demonstrate a critical role of cellular crosstalk for altered immune response, metabolism, and vasculature in AD. The glia associated genetic risk factors include APOE, TREM2, CD33, PGRN, CR1, and NLRP3, which correlate with the deposition and altered phagocytosis of Aβ. Moreover, aging-dependent downregulation of astrocyte and microglial Aβ-degrading enzymes limits the neurotrophic and neurogenic role of glial cells and inhibits lysosomal degradation and clearance of Aβ. Microglial cells secrete IGF-1, and neurons show a reduced responsiveness to the neurotrophic IGF-1R/IRS-2/PI3K signaling pathway, generating amyloidogenic and vascular dyshomeostasis in AD. Glial signals connect to neural stem cells, and a shift in glial phenotype over the AD trajectory even affects adult neurogenesis and the neurovascular niche. Overall, the current review informs about the interaction of neuronal and glial cell types in AD pathogenesis and its critical association with cerebrovascular dysfunction.

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Race-Related Association between APOE Genotype and Alzheimer’s Disease: A Systematic Review and Meta-Analysis

Journal of Alzheimer s Disease ◽

10.3233/jad-210549 ◽

2021 ◽

pp. 1-10

Author(s):

Wei Qin ◽

Wenwen Li ◽

Qi Wang ◽

Min Gong ◽

Tingting Li ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Black People ◽

Late Onset ◽

Meta Analysis ◽

Group Analysis ◽

Apoe Genotype ◽

Cochrane Library ◽

Data Sets ◽

Apoe Genotypes

Background: The global race-dependent association of Alzheimer’s disease (AD) and apolipoprotein E (APOE) genotype is not well understood. Transethnic analysis of APOE could clarify the role of genetics in AD risk across populations. Objective: This study aims to determine how race and APOE genotype affect the risks for AD. Methods: We performed a systematic search of PubMed, Embase, Web of Science, and the Cochrane Library since 1993 to Aug 25, 2020. A total of 10,395 reports were identified, and 133 were eligible for analysis with data on 77,402 participants. Studies contained AD clinical diagnostic and APOE genotype data. Homogeneous data sets were pooled in case-control analyses. Odds ratios and 95% confidence intervals for developing AD were calculated for populations of different races and APOE genotypes. Results: The proportion of APOE genotypes and alleles differed between populations of different races. Results showed that APOE ɛ4 was a risk factor for AD, whereas APOE ɛ2 protected against it. The effects of APOE ɛ4 and ɛ2 on AD risk were distinct in various races, they were substantially attenuated among Black people. Sub-group analysis found a higher frequency of APOE ɛ4/ɛ4 and lower frequency of APOE ɛ3/ɛ3 among early-onset AD than late-onset AD in a combined group and different races. Conclusion: Our meta-analysis suggests that the association of APOE genotypes and AD differ between races. These results enhance our understanding of APOE-related risk for AD across race backgrounds and provide new insights into precision medicine for AD.

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Breast Cancer, Alzheimer’s Disease, and APOE4 Allele in the UK Biobank Cohort

Journal of Alzheimer s Disease Reports ◽

10.3233/adr-200266 ◽

2021 ◽

Vol 5 (1) ◽

pp. 49-53

Author(s):

Steven Lehrer ◽

Peter H. Rheinstein

Keyword(s):

Breast Cancer ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Apoe Genotype ◽

Uk Biobank ◽

Breast Cancer Patients ◽

Apoe4 Allele ◽

Significant Difference ◽

The Uk ◽

Cognitive Problems

Background: Cognitive problems are common in breast cancer patients. The apolipoprotein E4 (APOE4) gene, a risk factor for Alzheimer’s disease (AD), may be associated with cancer-related cognitive decline. Objective: To further evaluate the effects of the APOE4 allele, we studied a cohort of patients from the UK Biobank (UKB) who had breast cancer; some also had AD. Methods: Our analysis included all subjects with invasive breast cancer. Single nucleotide polymorphism (SNP) data for rs 429358 and rs 7412 was used to determine APOE genotypes. Cognitive function as numeric memory was assessed with an online test (UKB data field 20240). Results: We analyzed data from 2,876 women with breast cancer. Of the breast cancer subjects, 585 (20%) carried the APOE4 allele. Numeric memory scores were significantly lower in APOE4 carriers and APOE4 homozygotes than non-carriers (p = 0.046). 34 breast cancer subjects (1.1%) had AD. There was no significant difference in survival among genotypes ɛ3/ɛ3, ɛ3/ɛ4, and ɛ4/ɛ4. Conclusion: UKB data suggest that cognitive problems in women with breast cancer are, for the most part, mild, compared with other sequelae of the disease. AD, the worst cognitive problem, is relatively rare (1.1%) and, when it occurs, APOE genotype has little impact on survival.

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ApoE genotype and familial Alzheimer's disease: a possible influence on age of onset in APP717 Val → Ile mutated families

Neuroscience Letters ◽

10.1016/0304-3940(94)11100-w ◽

1995 ◽

Vol 183 (1-2) ◽

pp. 1-3 ◽

Cited By ~ 30

Author(s):

Benedetta Nacmias ◽

Stefania Latorraca ◽

Patrizia Piersanti ◽

Paolo Forleo ◽

Silvia Piacentini ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Age Of Onset ◽

Apoe Genotype ◽

Familial Alzheimer’S Disease ◽

Familial Alzheimer's Disease

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Decline in verbal memory during preclinical Alzheimer's disease: Examination of the effect of APOE genotype

Journal of the International Neuropsychological Society ◽

10.1017/s1355617702870096 ◽

2002 ◽

Vol 8 (7) ◽

pp. 943-955 ◽

Cited By ~ 65

Author(s):

KELLY L. LANGE ◽

MARK W. BONDI ◽

DAVID P. SALMON ◽

DOUGLAS GALASKO ◽

DEAN C. DELIS ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Older Adults ◽

Alzheimer's Disease ◽

Episodic Memory ◽

Verbal Memory ◽

Verbal Learning ◽

Apoe Genotype ◽

Apoe Ε4 ◽

Dementia Syndrome ◽

Ε4 Allele

A subtle decline in episodic memory often occurs prior to the emergence of the full dementia syndrome in nondemented older adults who develop Alzheimer's disease (AD). The APOE-ε4 genotype may engender a more virulent form of AD that hastens this decline. To examine this possibility, we compared the rate of decline in episodic memory during the preclinical phase of AD in individuals with or without at least one APOE ε4 allele. Nondemented normal control (NC; n = 84) participants, nondemented older adults who subsequently developed dementia within 1 or 2 years (i.e., preclinical AD; n = 20), and patients with mild AD (n = 53) were examined with 2 commonly employed tests of episodic memory, the Logical Memory subtest of the Wechsler Memory Scale–Revised and the California Verbal Learning Test. Results revealed a precipitous decline in verbal memory abilities 1 to 2 years prior to the onset of the dementia syndrome, but there was little effect of APOE genotype on the rate of this memory decline. The presence of an APOE-ε4 allele, however, did have a differential effect on the sensitivity of the 2 types of memory tests for tracking progression and made an independent contribution to the prediction of conversion to AD. (JINS, 2002, 8, 943–955.)

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