The role of perivascular innervation and neurally mediated vasoreactivity in the pathophysiology of Alzheimer's disease

2017 ◽  
Vol 131 (12) ◽  
pp. 1207-1214 ◽  
Author(s):  
Shereen Nizari ◽  
Ignacio A. Romero ◽  
Cheryl A. Hawkes
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Vascular Tone ◽  
Neurovascular Unit ◽  
Efficient Removal ◽  
Amyloid Aβ ◽  
Β Amyloid ◽  
Considerable Work ◽  
The Brain

Neuronal death is a hallmark of Alzheimer's disease (AD) and considerable work has been done to understand how the loss of interconnectivity between neurons contributes to the associated dementia. Often overlooked however, is how the loss of neuronal innervation of blood vessels, termed perivascular innervation, may also contribute to the pathogenesis of AD. There is now considerable evidence supporting a crucial role for the neurovascular unit (NVU) in mediating the clearance of the β-amyloid (Aβ) peptide, one of the main pathological constituents of AD, from the brain. Moreover, efficient removal appears to be dependent on the communication of cells within the NVU to maintain adequate vascular tone and pulsatility. This review summarizes the composition of the NVU, including the sources of perivascular innervation and how the NVU mediates Aβ clearance from the brain. It also explores evidence supporting the hypothesis that loss of neurally mediated vasoreactivity contributes to Aβ pathology in the AD brain.

scholarly journals A lipid-invasion model for Alzheimer’s Disease

2019 ◽  
Author(s):  
Jonathan D Rudge
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Late Onset ◽  
Principal Role ◽  
Lipid Droplet Formation ◽  
Invasion Model ◽  
Β Amyloid ◽  
Mass Influx ◽  
The Brain

This paper describes a potential new explanation for Alzheimer’s disease (AD), referred to here as the lipid-invasion model. It proposes that AD is primarily caused by the influx of lipids following the breakdown of the blood brain barrier (BBB). The model argues that a principal role of the BBB is to protect the brain from external lipid access. When the BBB is damaged, it allows a mass influx of (mainly albumin-bound) free fatty acids (FFAs) and lipid-rich lipoproteins to the brain, which in turn causes neurodegeneration, amyloidosis, tau tangles and other AD characteristics. The model also argues that, whilst β-amyloid causes neurodegeneration, as is widely argued, its principal role in the disease lies in damaging the BBB. It is the external lipids, entering as a consequence, that are the primary drivers of neurodegeneration in AD., especially FFAs, which induce oxidative stress, stimulate microglia-driven neuroinflammation, and inhibit neurogenesis. Simultaneously, the larger, more lipid-laden lipoproteins, characteristic of the external plasma but not the CNS, cause endosomal-lysosomal abnormalities, amyloidosis and the formation of tau tangles, all characteristic of AD. In most cases (certainly in late-onset, noninherited forms of the disease) amyloidosis and tau tangle formation are consequences of this external lipid invasion, and in many ways more symptomatic of the disease than causative. In support of this, it is argued that the pattern of damage caused by the influx of FFAs into the brain is likely to resemble the neurodegeneration seen in alcohol-related brain damage (ARBD), a disease that shows many similarities to AD, including the areas of the brain it affects. The fact that neurodegeneration is far more pronounced in AD than in ARBD, and characterised by other features, such as amyloidosis and tau tangles, most likely results from the greater heterogeneity of the lipid assault in AD compared with ethanol alone. The lipid-invasion model, described here, arguably provides the first cohesive, multi-factorial explanation of AD that accounts for all currently known major risk factors, and explains all AD-associated pathologies, including those, such as endosomal-lysosomal dysfunction and excessive lipid droplet formation, that are not well-accounted for in other explanation of this disease.

scholarly journals Editorial for the Genetics of Alzheimer’s Disease Special Issue: October 2021

Genes ◽  
2021 ◽  
Vol 12 (11) ◽  
pp. 1794
Author(s):  
Laura Ibanez ◽  
Justin B. Miller
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Gray Matter ◽  
Neuronal Death ◽  
Tau Proteins ◽  
Special Issue ◽  
Amyloid Aβ ◽  
Β Amyloid ◽  
The Brain

Alzheimer’s disease is a complex and multifactorial condition regulated by both genetics and lifestyle, which ultimately results in the accumulation of β-amyloid (Aβ) and tau proteins in the brain, loss of gray matter, and neuronal death [...]

scholarly journals A lipid-invasion model for Alzheimer’s Disease

2019 ◽  
Author(s):  
Jonathan D Rudge
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Late Onset ◽  
Principal Role ◽  
Lipid Droplet Formation ◽  
Invasion Model ◽  
Β Amyloid ◽  
Mass Influx ◽  
The Brain

This paper describes a potential new explanation for Alzheimer’s disease (AD), referred to here as the lipid-invasion model. It proposes that AD is primarily caused by the influx of lipids following the breakdown of the blood brain barrier (BBB). The model argues that a principal role of the BBB is to protect the brain from external lipid access. When the BBB is damaged, it allows a mass influx of (mainly albumin-bound) free fatty acids (FFAs) and lipid-rich lipoproteins to the brain, which in turn causes neurodegeneration, amyloidosis, tau tangles and other AD characteristics. The model also argues that, whilst β-amyloid causes neurodegeneration, as is widely argued, its principal role in the disease lies in damaging the BBB. It is the external lipids, entering as a consequence, that are the primary drivers of neurodegeneration in AD., especially FFAs, which induce oxidative stress, stimulate microglia-driven neuroinflammation, and inhibit neurogenesis. Simultaneously, the larger, more lipid-laden lipoproteins, characteristic of the external plasma but not the CNS, cause endosomal-lysosomal abnormalities, amyloidosis and the formation of tau tangles, all characteristic of AD. In most cases (certainly in late-onset, noninherited forms of the disease) amyloidosis and tau tangle formation are consequences of this external lipid invasion, and in many ways more symptomatic of the disease than causative. In support of this, it is argued that the pattern of damage caused by the influx of FFAs into the brain is likely to resemble the neurodegeneration seen in alcohol-related brain damage (ARBD), a disease that shows many similarities to AD, including the areas of the brain it affects. The fact that neurodegeneration is far more pronounced in AD than in ARBD, and characterised by other features, such as amyloidosis and tau tangles, most likely results from the greater heterogeneity of the lipid assault in AD compared with ethanol alone. The lipid-invasion model, described here, arguably provides the first cohesive, multi-factorial explanation of AD that accounts for all currently known major risk factors, and explains all AD-associated pathologies, including those, such as endosomal-lysosomal dysfunction and excessive lipid droplet formation, that are not well-accounted for in other explanation of this disease.

scholarly journals Functional Foods: An Approach to Modulate Molecular Mechanisms of Alzheimer’s Disease

Cells ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 2347
Author(s):  
Anna Atlante ◽  
Giuseppina Amadoro ◽  
Antonella Bobba ◽  
Valentina Latina
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Molecular Mechanisms ◽  
Food Product ◽  
Neuroprotective Effects ◽  
The Road ◽  
Beneficial Effects ◽  
Β Amyloid ◽  
The Brain

A new epoch is emerging with intense research on nutraceuticals, i.e., “food or food product that provides medical or health benefits including the prevention and treatment of diseases”, such as Alzheimer’s disease. Nutraceuticals act at different biochemical and metabolic levels and much evidence shows their neuroprotective effects; in particular, they are able to provide protection against mitochondrial damage, oxidative stress, toxicity of β-amyloid and Tau and cell death. They have been shown to influence the composition of the intestinal microbiota significantly contributing to the discovery that differential microorganisms composition is associated with the formation and aggregation of cerebral toxic proteins. Further, the routes of interaction between epigenetic mechanisms and the microbiota–gut–brain axis have been elucidated, thus establishing a modulatory role of diet-induced epigenetic changes of gut microbiota in shaping the brain. This review examines recent scientific literature addressing the beneficial effects of some natural products for which mechanistic evidence to prevent or slowdown AD are available. Even if the road is still long, the results are already exceptional.

scholarly journals Pharmacogenetic features of cathepsin B inhibitors that improve memory deficit and reduce β-amyloid related to Alzheimer's disease

2010 ◽  
Vol 391 (8) ◽  
Author(s):  
Vivian Hook ◽  
Gregory Hook ◽  
Mark Kindy
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Models ◽  
Cathepsin B ◽  
Memory Deficit ◽  
Mutant Site ◽  
Amyloid Aβ ◽  
Β Amyloid ◽  
The Brain ◽  
Aβ Production

Abstract Beta-amyloid (Aβ) in the brain is a major factor involved in Alzheimer's disease (AD) that results in severe memory deficit. Our recent studies demonstrate pharmacogenetic differences in the effects of inhibitors of cathepsin B to improve memory and reduce Aβ in different mouse models of AD. The inhibitors improve memory and reduce brain Aβ in mice expressing the wild-type (WT) β-secretase site of human APP, expressed in most AD patients. However, these inhibitors have no effect in mice expressing the rare Swedish (Swe) mutant amyloid precursor protein (APP). Knockout of the cathepsin B decreased brain Aβ in mice expressing WT APP, validating cathepsin B as the target. The specificity of cathepsin B to cleave the WT β-secretase site, but not the Swe mutant site, of APP for Aβ production explains the distinct inhibitor responses in the different AD mouse models. In contrast to cathepsin B, the BACE1 β-secretase prefers to cleave the Swe mutant site. Discussion of BACE1 data in the field indicate that they do not preclude cathepsin B as also being a β-secretase. Cathepsin B and BACE1 could participate jointly as β-secretases. Significantly, the majority of AD patients express WT APP and, therefore, inhibitors of cathepsin B represent candidate drugs for AD.

The role of neurovascular unit damage in the occurrence and development of Alzheimer’s disease

2019 ◽  
Vol 30 (5) ◽  
pp. 477-484 ◽  
Author(s):  
Xin Liu ◽  
DeRen Hou ◽  
FangBo Lin ◽  
Jing Luo ◽  
JingWen Xie ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Tau Protein ◽  
Senile Dementia ◽  
Neurovascular Unit ◽  
Common Type ◽  
Pathological Changes ◽  
Β Amyloid ◽  
Progressive Cognitive Impairment

Abstract Alzheimer’s disease (AD) is a neurodegenerative disease with progressive cognitive impairment. It is the most common type of senile dementia, accounting for 65%–70% of senile dementia [Alzheimer’s Association (2016). 2016 Alzheimer’s disease facts and figures. Alzheimers Dement. 12, 459–509]. At present, the pathogenesis of AD is still unclear. It is considered that β-amyloid deposition, abnormal phosphorylation of tau protein, and neurofibrillary tangles are the basic pathological changes of AD. However, the role of neurovascular unit damage in the pathogenesis of AD has been attracting more and more attention in recent years. The composition of neurovascular unit and the role of neurovascular unit damage in the occurrence and development of AD were reviewed in this paper.

scholarly journals A lipid-leakage model for Alzheimer’s Disease

2019 ◽  
Author(s):  
Jonathan D Rudge
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Fatty Acids ◽  
Anterograde Amnesia ◽  
Principal Role ◽  
Leakage Model ◽  
Β Amyloid ◽  
Mass Influx ◽  
The Brain

This paper describes a potential new explanation for Alzheimer’s disease (AD), referred to here as the lipid leakage model. It proposes that AD is caused by the influx of lipids following the breakdown of the blood brain barrier (BBB).The model argues that a principle role of the BBB is to protect the brain from external lipid access. When the BBB is damaged, it allows a mass influx of free fatty acids (FFAs) and lipid-rich lipoproteins to the brain, which in turn causes neurodegeneration, amyloidosis, tau tangles and other AD characteristics. The model also argues that, whilst β-amyloid causes neurodegeneration, as is widely argued, its principal role in the disease lies in damaging the BBB. It is the external lipids, entering as a consequence, that are the primary drivers of neurodegeneration in AD, especially FFAs, which stimulate microglia-driven neuroinflammation, inhibit neurogenesis and cause endosomal-lysosomal abnormalities, all characteristic of AD. In most cases amyloidosis and tau tangle formation lie downstream of these lipids and are in many ways as much symptomatic of the disease as causative. In support of this, it is argued that the pattern of damage caused by the influx of FFAs into the brain is likely to resemble the neurodegeneration seen in alcohol-related brain damage (ARBD), a disease that shows many similarities to AD, including the areas of the brain it affects. The fact that anterograde amnesia is far more pronounced in AD than ARBD results from the greater hydrophobicity of FFAs, in an anaesthesia-related manner.

Key Peptides and Proteins in Alzheimer’s Disease

2019 ◽  
Vol 20 (6) ◽  
pp. 577-599 ◽  
Author(s):  
Botond Penke ◽  
Ferenc Bogár ◽  
Gábor Paragi ◽  
János Gera ◽  
Lívia Fülöp
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Physiological Role ◽  
Progressive Dementia ◽  
Future Directions ◽  
Cellular Receptors ◽  
Amyloid Aβ ◽  
Β Amyloid ◽  
Proteins And Peptides

Alzheimer’s Disease (AD) is a form of progressive dementia involving cognitive impairment, loss of learning and memory. Different proteins (such as amyloid precursor protein (APP), β- amyloid (Aβ) and tau protein) play a key role in the initiation and progression of AD. We review the role of the most important proteins and peptides in AD pathogenesis. The structure, biosynthesis and physiological role of APP are shortly summarized. The details of trafficking and processing of APP to Aβ, the cytosolic intracellular Aβ domain (AICD) and small soluble proteins are shown, together with other amyloid-forming proteins such as tau and α-synuclein (α-syn). Hypothetic physiological functions of Aβ are summarized. The mechanism of conformational change, the formation and the role of neurotoxic amyloid oligomeric (oAβ) are shown. The fibril formation process and the co-existence of different steric structures (U-shaped and S-shaped) of Aβ monomers in mature fibrils are demonstrated. We summarize the known pathogenic and non-pathogenic mutations and show the toxic interactions of Aβ species after binding to cellular receptors. Tau phosphorylation, fibrillation, the molecular structure of tau filaments and their toxic effect on microtubules are shown. Development of Aβ and tau imaging in AD brain and CSF as well as blood biomarkers is shortly summarized. The most probable pathomechanisms of AD including the toxic effects of oAβ and tau; the three (biochemical, cellular and clinical) phases of AD are shown. Finally, the last section summarizes the present state of Aβ- and tau-directed therapies and future directions of AD research and drug development.

Current theories for the molecular and cellular pathogenesis of Alzheimer's disease

2001 ◽  
Vol 3 (16) ◽  
pp. 1-11 ◽  
Author(s):  
Gunnar K. Gouras
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Disease Process ◽  
Amyloid Aβ ◽  
Β Amyloid ◽  
Cellular Pathogenesis ◽  
Amyloid Cascade ◽  
The Brain ◽  
Aβ Production ◽  
Prevailing View

Over the past decade, the prevailing view for the molecular and cellular pathogenesis of Alzheimer's disease (AD) has centred on the β-amyloid (Aβ) peptide that accumulates in vulnerable brain areas in the disease. The amyloid cascade hypothesis postulates that the build up of Aβ in the brain causes damage to neurons, leading to dysfunction and loss of neurons, and the clinical phenotype of the amnestic dementia characteristic of AD. All known mutations that result in autosomal dominant forms of early-onset familial AD cause increased production of Aβ42, a form of Aβ that is particularly relevant in AD. Other proteins that are crucial to the pathogenesis of AD are the presenilins 1 and 2, which are intimately involved with Aβ production and when mutated in familial forms of AD cause increases in Aβ42. Currently, challenges in AD research include determining the earliest pathological effects of Aβ42, how the important AD risk factor apolipoprotein E affects the disease process, whether presenilin is the elusive γ-secretase, and how levels of Aβ can be effectively reduced therapeutically.

Sign in / Sign up

Export Citation Format

Share Document