The non Amyloid-β Component (NAC) of Human α-Synuclein Oligomers Induces the Formation of New Aβ Oligomers: Insight into the Molecular Interactions that Link Parkinson's Disease and Alzheimer's Disease

Abstract The endotoxin hypothesis of neurodegeneration is the hypothesis that endotoxin causes or contributes to neurodegeneration. Endotoxin is a lipopolysaccharide (LPS), constituting much of the outer membrane of gram-negative bacteria, present at high concentrations in gut, gums and skin and in other tissue during bacterial infection. Blood plasma levels of endotoxin are normally low, but are elevated during infections, gut inflammation, gum disease and neurodegenerative disease. Adding endotoxin at such levels to blood of healthy humans induces systemic inflammation and brain microglial activation. Adding high levels of endotoxin to the blood or body of rodents induces microglial activation, priming and/or tolerance, memory deficits and loss of brain synapses and neurons. Endotoxin promotes amyloid β and tau aggregation and neuropathology, suggesting the possibility that endotoxin synergises with different aggregable proteins to give different neurodegenerative diseases. Blood and brain endotoxin levels are elevated in Alzheimer’s disease, which is accelerated by systemic infections, including gum disease. Endotoxin binds directly to APOE, and the APOE4 variant both sensitises to endotoxin and predisposes to Alzheimer’s disease. Intestinal permeability increases early in Parkinson’s disease, and injection of endotoxin into mice induces α-synuclein production and aggregation, as well as loss of dopaminergic neurons in the substantia nigra. The gut microbiome changes in Parkinson’s disease, and changing the endotoxin-producing bacterial species can affect the disease in patients and mouse models. Blood endotoxin is elevated in amyotrophic lateral sclerosis, and endotoxin promotes TDP-43 aggregation and neuropathology. Peripheral diseases that elevate blood endotoxin, such as sepsis, AIDS and liver failure, also result in neurodegeneration. Endotoxin directly and indirectly activates microglia that damage neurons via nitric oxide, oxidants and cytokines, and by phagocytosis of synapses and neurons. The endotoxin hypothesis is unproven, but if correct, then neurodegeneration may be reduced by decreasing endotoxin levels or endotoxin-induced neuroinflammation.

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Impaired retrograde transport of axonal autophagosomes contributes to autophagic stress in Alzheimer’s disease neurons

eLife ◽

10.7554/elife.21776 ◽

2017 ◽

Vol 6 ◽

Cited By ~ 44

Author(s):

Prasad Tammineni ◽

Xuan Ye ◽

Tuancheng Feng ◽

Daniyal Aikal ◽

Qian Cai

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Amyloid Β ◽

Retrograde Transport ◽

Presynaptic Terminals ◽

Aβ Oligomers ◽

Autophagic Vacuoles ◽

Axonal Pathology ◽

Mechanistic Insight ◽

Insight Into

Neurons face unique challenges of transporting nascent autophagic vacuoles (AVs) from distal axons toward the soma, where mature lysosomes are mainly located. Autophagy defects have been linked to Alzheimer’s disease (AD). However, the mechanisms underlying altered autophagy remain unknown. Here, we demonstrate that defective retrograde transport contributes to autophagic stress in AD axons. Amphisomes predominantly accumulate at axonal terminals of mutant hAPP mice and AD patient brains. Amyloid-β (Aβ) oligomers associate with AVs in AD axons and interact with dynein motors. This interaction impairs dynein recruitment to amphisomes through competitive interruption of dynein-Snapin motor-adaptor coupling, thus immobilizing them in distal axons. Consistently, deletion of Snapin in mice causes AD-like axonal autophagic stress, whereas overexpressing Snapin in hAPP neurons reduces autophagic accumulation at presynaptic terminals by enhancing AV retrograde transport. Altogether, our study provides new mechanistic insight into AD-associated autophagic stress, thus establishing a foundation for ameliorating axonal pathology in AD.

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Soluble TREM2 is elevated in Parkinson’s disease subgroups with increased CSF tau

Brain ◽

10.1093/brain/awaa021 ◽

2020 ◽

Vol 143 (3) ◽

pp. 932-943 ◽

Cited By ~ 2

Author(s):

Edward N Wilson ◽

Michelle S Swarovski ◽

Patricia Linortner ◽

Marian Shahid ◽

Abigail J Zuckerman ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Parkinson’S Disease ◽

Alzheimer's Disease ◽

Parkinson's Disease ◽

Cognitive Impairment ◽

Amyloid Β ◽

Soluble Form ◽

Elderly Subjects ◽

Csf Biomarker ◽

Biomarker Signature

Abstract Parkinson’s disease is the second most common neurodegenerative disease after Alzheimer’s disease and affects 1% of the population above 60 years old. Although Parkinson’s disease commonly manifests with motor symptoms, a majority of patients with Parkinson’s disease subsequently develop cognitive impairment, which often progresses to dementia, a major cause of morbidity and disability. Parkinson’s disease is characterized by α-synuclein accumulation that frequently associates with amyloid-β and tau fibrils, the hallmarks of Alzheimer’s disease neuropathological changes; this co-occurrence suggests that onset of cognitive decline in Parkinson’s disease may be associated with appearance of pathological amyloid-β and/or tau. Recent studies have highlighted the appearance of the soluble form of the triggering receptor expressed on myeloid cells 2 (sTREM2) receptor in CSF during development of Alzheimer’s disease. Given the known association of microglial activation with advancing Parkinson’s disease, we investigated whether CSF and/or plasma sTREM2 differed between CSF biomarker-defined Parkinson’s disease participant subgroups. In this cross-sectional study, we examined 165 participants consisting of 17 cognitively normal elderly subjects, 45 patients with Parkinson’s disease with no cognitive impairment, 86 with mild cognitive impairment, and 17 with dementia. Stratification of subjects by CSF amyloid-β and tau levels revealed that CSF sTREM2 concentrations were elevated in Parkinson’s disease subgroups with a positive tau CSF biomarker signature, but not in Parkinson’s disease subgroups with a positive CSF amyloid-β biomarker signature. These findings indicate that CSF sTREM2 could serve as a surrogate immune biomarker of neuronal injury in Parkinson’s disease.

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The Role of Lysosomes in a Broad Disease-Modifying Approach Evaluated across Transgenic Mouse Models of Alzheimer’s Disease and Parkinson’s Disease and Models of Mild Cognitive Impairment

International Journal of Molecular Sciences ◽

10.3390/ijms20184432 ◽

2019 ◽

Vol 20 (18) ◽

pp. 4432 ◽

Cited By ~ 3

Author(s):

Jeannie Hwang ◽

Candice M. Estick ◽

Uzoma S. Ikonne ◽

David Butler ◽

Morgan C. Pait ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Parkinson’S Disease ◽

Alzheimer's Disease ◽

Parkinson's Disease ◽

Cognitive Impairment ◽

Mild Cognitive Impairment ◽

Amyloid Β ◽

Age Related ◽

Disease Modifying

Many neurodegenerative disorders have lysosomal impediments, and the list of proposed treatments targeting lysosomes is growing. We investigated the role of lysosomes in Alzheimer’s disease (AD) and other age-related disorders, as well as in a strategy to compensate for lysosomal disturbances. Comprehensive immunostaining was used to analyze brains from wild-type mice vs. amyloid precursor protein/presenilin-1 (APP/PS1) mice that express mutant proteins linked to familial AD. Also, lysosomal modulation was evaluated for inducing synaptic and behavioral improvements in transgenic models of AD and Parkinson’s disease, and in models of mild cognitive impairment (MCI). Amyloid plaques were surrounded by swollen organelles positive for the lysosome-associated membrane protein 1 (LAMP1) in the APP/PS1 cortex and hippocampus, regions with robust synaptic deterioration. Within neurons, lysosomes contain the amyloid β 42 (Aβ42) degradation product Aβ38, and this indicator of Aβ42 detoxification was augmented by Z-Phe-Ala-diazomethylketone (PADK; also known as ZFAD) as it enhanced the lysosomal hydrolase cathepsin B (CatB). PADK promoted Aβ42 colocalization with CatB in lysosomes that formed clusters in neurons, while reducing Aβ deposits as well. PADK also reduced amyloidogenic peptides and α-synuclein in correspondence with restored synaptic markers, and both synaptic and cognitive measures were improved in the APP/PS1 and MCI models. These findings indicate that lysosomal perturbation contributes to synaptic and cognitive decay, whereas safely enhancing protein clearance through modulated CatB ameliorates the compromised synapses and cognition, thus supporting early CatB upregulation as a disease-modifying therapy that may also slow the MCI to dementia continuum.

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CSF amyloid-β-peptides in Alzheimer's disease, dementia with Lewy bodies and Parkinson's disease dementia

Brain ◽

10.1093/brain/awl063 ◽

2006 ◽

Vol 129 (5) ◽

pp. 1177-1187 ◽

Cited By ~ 129

Author(s):

Mirko Bibl ◽

Brit Mollenhauer ◽

Hermann Esselmann ◽

Piotr Lewczuk ◽

Hans-Wolfgang Klafki ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Parkinson’S Disease ◽

Alzheimer's Disease ◽

Parkinson's Disease ◽

Dementia With Lewy Bodies ◽

Lewy Bodies ◽

Amyloid Β ◽

Parkinson’S Disease Dementia ◽

Alzheimer’S Disease Dementia

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Target Enzymes Considered for the Treatment of Alzheimer’s Disease and Parkinson’s Disease

BioMed Research International ◽

10.1155/2020/2010728 ◽

2020 ◽

Vol 2020 ◽

pp. 1-14

Author(s):

Namdoo Kim ◽

Hyuck Jin Lee

Keyword(s):

Alzheimer’S Disease ◽

Parkinson’S Disease ◽

Alzheimer's Disease ◽

Parkinson's Disease ◽

Amyloid Β ◽

Biological Molecules ◽

Insulin Degrading Enzyme ◽

Multiple Risk Factors ◽

Amyloidogenic Proteins ◽

Chemical Agents

Various amyloidogenic proteins have been suggested to be involved in the onset and progression of neurodegenerative diseases (ND) such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). Particularly, the aggregation of misfolded amyloid-β and hyperphosphorylated tau and α-synuclein are linked to the pathogenesis of AD and PD, respectively. In order to care the diseases, multiple small molecules have been developed to regulate the aggregation pathways of these amyloid proteins. In addition to controlling the aggregation of amyloidogenic proteins, maintaining the levels of the proteins in the brain by amyloid degrading enzymes (ADE; neprilysin (NEP), insulin-degrading enzyme (IDE), asparagine endopeptidase (AEP), and ADAM10) is also essential to cure AD and PD. Therefore, numerous biological molecules and chemical agents have been investigated as either inducer or inhibitor against the levels and activities of ADE. Although the side effect of enhancing the activity of ADE could occur, the removal of amyloidogenic proteins could result in a relatively good strategy to treat AD and PD. Furthermore, since the causes of ND are diverse, various multifunctional (multitarget) chemical agents have been designed to control the actions of multiple risk factors of ND, including amyloidogenic proteins, metal ions, and reactive oxygen species. Many of them, however, were invented without considerations of regulating ADE levels and actions. Incorporation of previously created molecules with the chemical agents handling ADE could be a promising way to treat AD and PD. This review introduces the ADE and molecules capable of modulating the activity and expression of ADE.

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Potential Benefits of Nobiletin, A Citrus Flavonoid, against Alzheimer’s Disease and Parkinson’s Disease

International Journal of Molecular Sciences ◽

10.3390/ijms20143380 ◽

2019 ◽

Vol 20 (14) ◽

pp. 3380 ◽

Cited By ~ 11

Author(s):

Akira Nakajima ◽

Yasushi Ohizumi

Keyword(s):

Alzheimer’S Disease ◽

Parkinson’S Disease ◽

Alzheimer's Disease ◽

Parkinson's Disease ◽

Animal Models ◽

Neurodegenerative Disease ◽

Cognitive Deficits ◽

Amyloid Β ◽

Neuroprotective Activity ◽

Substantia Nigra Pars Compacta

Alzheimer’s disease (AD), which is characterized by the presence of amyloid-β (Aβ) plaques and neurofibrillary tangles, accompanied by neurodegeneration, is the most common form of age-related neurodegenerative disease. Parkinson’s disease (PD) is the second most common neurodegenerative disease after AD, and is characterized by early prominent loss of dopaminergic neurons in the substantia nigra pars compacta. As currently available treatments are not able to significantly alter the progression of these diseases, successful therapeutic and preventive interventions are strongly needed. In the course of our survey of substances from natural resources having anti-dementia and neuroprotective activity, we found nobiletin, a polymethoxylated flavone from the peel of Citrus depressa. Nobiletin improved cognitive deficits and the pathological features of AD, such as Aβ pathology, hyperphosphorylation of tau, and oxidative stress, in animal models of AD. In addition, nobiletin improved motor and cognitive deficits in PD animal models. These observations suggest that nobiletin has the potential to become a novel drug for the treatment and prevention of neurodegenerative diseases such as AD and PD.

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Neuropathological and Biomarker Findings in Parkinson’s Disease and Alzheimer’s Disease: From Protein Aggregates to Synaptic Dysfunction

Journal of Parkinson s Disease ◽

10.3233/jpd-202323 ◽

2020 ◽

pp. 1-15

Author(s):

Yaroslau Compta ◽

Tamas Revesz

Keyword(s):

Alzheimer’S Disease ◽

Parkinson’S Disease ◽

Alzheimer's Disease ◽

Parkinson's Disease ◽

Amyloid Β ◽

Protein Aggregates ◽

Amyloid Β Peptide ◽

Therapeutic Implications ◽

Positron Emission ◽

Synaptic Markers

There is mounting evidence that Parkinson’s disease (PD) and Alzheimer’s disease (AD) share neuropathological hallmarks, while similar types of biomarkers are being applied to both. In this review we aimed to explore similarities and differences between PD and AD at both the neuropathology and the biomarker levels, specifically focusing on protein aggregates and synapse dysfunction. Thus, amyloid-β peptide (Aβ) and tau lesions of the Alzheimer-type are common in PD and α-synuclein Lewy-type aggregates are frequent findings in AD. Modern neuropathological techniques adding to routine immunohistochemistry might take further our knowledge of these diseases beyond protein aggregates and down to their presynaptic and postsynaptic terminals, with potential mechanistic and even future therapeutic implications. Translation of neuropathological discoveries to the clinic remains challenging. Cerebrospinal fluid (CSF) and positron emission tomography (PET) markers of Aβ and tau have been shown to be reliable for AD diagnosis. Conversely, CSF markers of α-synuclein have not been that consistent. In terms of PET markers, there is no PET probe available for α-synuclein yet, while the AD PET markers range from consistent evidence of their specificity (amyloid imaging) to greater uncertainty of their reliability due to off-target binding (tau imaging). CSF synaptic markers are attractive, still needing more evidence, which currently suggests those might be non-specific markers of disease progression. It can be summarized that there is neuropathological evidence that protein aggregates of AD and PD are present both at the soma and the synapse. Thus, a number of CSF and PET biomarkers beyond α-synuclein, tau and Aβ might capture these different faces of protein-related neurodegeneration. It remains to be seen what the longitudinal outcomes and the potential value as surrogate markers of these biomarkers are.

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Alzheimer’s disease tau is a prominent pathology in LRRK2 Parkinson’s disease

Acta Neuropathologica Communications ◽

10.1186/s40478-019-0836-x ◽

2019 ◽

Vol 7 (1) ◽

Cited By ~ 21

Author(s):

Michael X. Henderson ◽

Medha Sengupta ◽

John Q. Trojanowski ◽

Virginia M. Y. Lee

Keyword(s):

Alzheimer’S Disease ◽

Parkinson’S Disease ◽

Alzheimer's Disease ◽

Parkinson's Disease ◽

Clinical Presentation ◽

Lewy Bodies ◽

Amyloid Β ◽

Tau Pathology ◽

Mutation Carriers ◽

Familial Parkinson’S Disease

AbstractMutations in leucine-rich repeat kinase 2 (LRRK2) are the most common cause of familial Parkinson’s disease (PD). While the clinical presentation of LRRK2 mutation carriers is similar to that of idiopathic PD (iPD) patients, the neuropathology of LRRK2 PD is less clearly defined. Lewy bodies (LBs) composed of α-synuclein are a major feature of iPD, but are not present in all LRRK2 PD cases. There is some evidence that tau may act as a neuropathological substrate in LB-negative LRRK2 PD, but this has not been examined systematically. In the current study, we examined α-synuclein, tau, and amyloid β (Aβ) pathologies in 12 LRRK2 mutation carriers. We find that α-synuclein pathology is present in 63.6% of LRRK2 mutation carriers, but tau pathology can be found in 100% of carriers and is abundant in 91% of carriers. We further use an antibody which selectively binds Alzheimer’s disease (AD)-type tau and use quantitative analysis of tau pathology to demonstrate that AD tau is the prominent type of tau present in LRRK2 mutation carriers. Abundant Aβ pathology can also be found in LRRK2 mutation carriers and is consistent with comorbid AD pathology. Finally, we assessed the association of neuropathology with clinical features in LRRK2 mutation carriers and idiopathic individuals and find that LRRK2 PD shares clinical and pathological features of idiopathic PD. The prevalence of AD-type tau pathology in LRRK2 PD is an important consideration for understanding PD pathogenesis and refining clinical trial inclusion and progression criterion.

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Glucagon-like Peptide 1, Brain, Neurodegenerative Diseases: A Modern View

Bulletin of Science and Practice ◽

10.33619/2414-2948/53/19 ◽

2020 ◽

Vol 6 (4) ◽

pp. 153-172

Author(s):

Bulgakova ◽

Romanchuk ◽

Treneva

Keyword(s):

Alzheimer’S Disease ◽

Parkinson’S Disease ◽

Alzheimer's Disease ◽

Parkinson's Disease ◽

Neurodegenerative Diseases ◽

Amyloid Β ◽

Amyloid Β Peptide ◽

Receptor Agonists ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1

Glucagon-like peptide 1, a hormone synthesized in the intestine, has attracted the attention of scientists with its connection with the brain. A number of studies have shown the effect of glucagon-like peptide 1 on the functions of the nervous system, such as thermogenesis, blood pressure control, energy homeostasis, neurogenesis. In addition, modulation of glucagon-like peptide 1 activity may affect the aggregation of amyloid β-peptide in Alzheimer’s disease and dopamine in Parkinson’s disease. Glucagon-like peptide 1 receptor agonists have shown a beneficial effect on animal brain ischemia by reducing the area of brain infarction, reducing neurological deficit due to inhibition of oxidative stress, apoptosis, and inflammatory response. Their positive effect on cognitive function in animals with type 2 diabetes mellitus or obesity has been proven, improving learning and memory. There is increasing evidence of the neuroprotective effect of glucagon-like peptide 1 receptor agonists in animals with neurodegenerative diseases, regardless of the presence of T2DM. However, further clinical studies are needed to study the feasibility of using these drugs to treat Parkinson’s disease, Alzheimer’s disease, and other forms of cognitive impairment in humans. The discussion of the above issues is the subject of this literature review.

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