Alzheimer’s diseas : Oxytocin can reverse Aβ-induced impairments

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Alzheimer’s disease is a progressive disorder in which the nerve cells (neurons) in a person’s brain and the connections among them degenerate slowly, causing severe memory loss, intellectual deficiencies, and deterioration in motor skills and communication.

One of the main causes of Alzheimer’s is the accumulation of a protein called amyloid β (Aβ) in clusters around neurons in the brain, which hampers their activity and triggers their degeneration.

Studies in animal models have found that increasing the aggregation of Aβ in the hippocampus – the brain’s main learning and memory center – causes a decline in the signal transmission potential of the neurons therein.

This degeneration affects a specific trait of the neurons, called ‘synaptic plasticity,’ which is the ability of synapses (the site of signal exchange between neurons) to adapt to an increase or decrease in signaling activity over time.

Synaptic plasticity is crucial to the development of learning and cognitive functions in the hippocampus. Thus, Aβ and its role in causing cognitive memory and deficits have been the focus of most research aimed at finding treatments for Alzheimer’s.

Now, advancing this research effort, a team of scientists from Japan, led by Professor Akiyoshi Saitoh from the Tokyo University of Science, has looked at oxytocin, a hormone conventionally known for its role in the female reproductive system and in inducing the feelings of love and well-being.

“Oxytocin was recently found to be involved in regulating learning and memory performance, but so far, no previous study deals with the effect of oxytocin on Aβ-induced cognitive impairment,” Prof Saitoh says. Realizing this, Prof Saitoh’s group set out to connect the dots.

Their findings are published in Biochemical and Biophysical Research Communication.

Prof Saitoh and team first perfused slices of the mouse hippocampus with Aβ to confirm that Aβ causes the signaling abilities of neurons in the slices to decline or – in other words – impairs their synaptic plasticity. Upon additional perfusion with oxytocin, however, the signaling abilities increased, suggesting that oxytocin can reverse the impairment of synaptic plasticity that Aβ causes.

To find out how oxytocin achieves this, they conducted a further series of experiments. In a normal brain, oxytocin acts by binding with special structures in the membranes of brain cells, called oxytocin receptors.

The scientists artificially ‘blocked’ these receptors in the mouse hippocampus slices to see if oxytocin could reverse Aβ-induced impairment of synaptic plasticity without binding to these receptors.

Expectedly, when the receptors were blocked, oxytocin could not reverse the effect of Aβ, which shows that these receptors are essential for oxytocin to act.

Oxytocin is known to facilitate certain cellular chemical activities that are important in strengthening neuronal signaling potential and formation of memories, such as influx of calcium ions.

Previous studies have suspected that Aβ suppresses some of these chemical activities. When the scientists artificially blocked these chemical activities, they found that addition of oxytocin addition to the hippocampal slices did not reverse the damage to synaptic plasticity caused by Aβ.

Additionally, they found that oxytocin itself does not have any effect on synaptic plasticity in the hippocampus, but it is somehow able to reverse the ill-effects of Aβ.

Prof Saitoh remarks, “This is the first study in the world that has shown that oxytocin can reverse Aβ-induced impairments in the mouse hippocampus.”

This is only a first step and further research remains to be conducted in vivo in animal models and then humans before sufficient knowledge can be gathered to reposition oxytocin into a drug for Alzheimer’s.

But, Prof Saitoh remains hopeful. He concludes, “At present, there are no sufficiently satisfactory drugs to treat dementia, and new therapies with novel mechanisms of action are desired.

Our study puts forth the interesting possibility that oxytocin could be a novel therapeutic modality for the treatment of memory loss associated with cognitive disorders such as Alzheimer’s disease.

We expect that our findings will open up a new pathway to the creation of new drugs for the treatment of dementia caused by Alzheimer’s disease.”


Several cardiovascular risk factors have long been associated with a greater risk for future cognitive decline in nondemented individuals (1).

Control of vascular risk factors effectively reduces the incidence of dementia in both healthy and cognitively impaired individuals (2). The presence of intracerebral atherosclerotic vascular disease (3) exacerbates all types of dementia and has been independently associated with worse cognitive performance even in nondemented individuals (4).

These observations indicate that the aging-related inflammatory nature of both atherosclerosis and dementia involves multiple common cellular and molecular mechanisms. Recent accumulating evidence points toward the existence of a possible nonexclusive shared systems biology process that may drive aging-associated diseases, atherosclerotic cardiovascular disease (CVD), and dementia (Figure 1).

Figure 1
Figure 1 – (A) Amyloid-beta (Aβ) 1-42 peptides have been found in brain parenchymal and cardiac depositions and, to a lesser extent, in vessels. Depositions composed of Αβ1-40 peptides have been described mainly in the heart and vessels including several vascular beds ranging from: (1) leptomeningeal and cortical vessels in cerebral amyloid angiopathy (CAA); to (2) cerebral microvasculature; (3) intracerebral arteries/circle of Willis; (4) carotid arteries; (5) aorta; and (6) coronary/extracerebral arteries. (B) Brain Αβ deposits trigger a number of events involved in neuronal dysfunction clinically manifested as cognitive decline and progressive Alzheimer’s type dementia. Cardiac depositions are associated with cardiomyocyte dysfunction. Vascular Αβ deposition induces functional changes (vascular stiffening) and promotes vascular inflammation and atherosclerosis. Aging-associated Αβ-induced cardiovascular disease leads to cerebral hypoperfusion, which is a risk factor for vascular, Alzheimer’s, or mixed dementia.

Production and accumulation of amyloid-beta (Aβ) peptides in the brain are considered the hallmark of Alzheimer’s disease (AD) amyloid hypothesis (5). The prototypic cerebrovascular disease associated with Αβ40 deposits is cerebral amyloid angiopathy (CAA) (6).

CAA describes a group of aging-associated brain disorders with characteristic pathological findings of amyloid deposits predominantly in the arteriolar wall.

Clinical and imaging features of CAA vary from asymptomatic microbleeds to severe hemorrhage, neurological deficits, cognitive impairment, dementia, and death. Defective perivascular drainage of neuronal-derived Aβ is probably the main mechanism of Αβ deposition. Among Aβ peptides, Αβ1-40 is the main peptide involved in the pathogenesis of CAA, whereas Αβ1-42 is mainly involved in development of AD.

The vascular preference of Aβ1-40 has led to the hypothesis that this molecule may exert proinflammatory properties not only in cerebral but also in peripheral vasculature, mediating arterial disease as depicted in Figure 1, suggesting a continuum of Aβ1-40 deposits in the circulatory system ranging from leptomeningeal and cortical cerebral microvasculature (CAA) to intracerebral, carotid, aortic, or coronary vascular wall or heart.

Interestingly, in contrast to studies examining associations between Aβ1-40 plasma levels and cardiovascular disease, studies assessing the association of plasma Αβ1-40 with cognitive function have not yielded consistent results (7).

The detrimental properties of Αβ1-40 species on vascular brain pathology affecting memory and cognition secondarily to microvasculature damage rather than through direct neurotoxicity, may explain this discrepancy.

In this review, we present contemporary evidence that links Αβ peptides with vascular inflammation and a wide range of associated extracerebral atherosclerotic manifestations and myocardial dysfunction, as well as adverse CVD outcomes and mortality (Central Illustration). Based on this evidence, we discuss the potential clinical utility of Αβ1-40 as a biomarker for risk stratification for mortality and present therapeutic interventions that may alter Αβ accumulation.

Central Illustration
Central Illustration
The Alzheimer’s Disease Amyloid-Beta Hypothesis in Cardiovascular Aging and Disease
Several factors alter APP/Aβ metabolism by promoting amyloidogenic pathways leading to increased Αβ1-40 blood levels. Subsequent deposition of Αβ1-40 in heart and vessels induces cell damage, accelerating arterial stiffening, atherosclerosis, and cardiac dysfunction, which are manifestations of cardiovascular aging and disease. Epidemiological evidence supports the clinical relevance of these effects. Αβ1-40 blood levels fulfill several criteria as a cardiovascular prognostic biomarker for risk stratification. Lifestyle and medical interventions interfere with Αβ1-40 levels. Aβ = amyloid-beta; APP = amyloid precursor protein; CVD = cardiovascular disease; SNP = single-nucleotide polymorphism.

Amyloid Precursor Protein and Aβ Metabolism

Aβ peptides are proteolytic fragments of amyloid precursor protein (APP), an integral membrane protein (8,9). The APP gene produces 3 major splice variants (10), APP695, APP751, and APP770, produced in neurons, endothelial cells, and platelets, respectively.

The exact physiological function of this well-conserved, site-specific APP/Αβ pathway is not fully elucidated, but it is associated with natural antimicrobial defense (11) and coagulation cascade proteolytic events (12). The latter is mediated by a Kunitz-type serine protease inhibitor domain contained in APP751 and APP770 molecules.

APP can be initially cleaved by α-secretases generating nonamyloidogenic products depending on its location on plasma membrane, the site of processing (membrane or endosomes), and environmental pH (13), or by β-secretases, also known as beta amyloid cleaving enzymes (BACE) (Figure 2).

The β-secretase–mediated cleavage of APP retains the integrity of Αβ fragments within the remaining C99 peptide, while C99 subsequent cleavage by γ-secretases releases Aβ peptides (14). C99 cutting site by γ-secretases depends on the location of processing (endosomes or Golgi network) and generates amino acid peptides of length 40 (Αβ1-40 mostly found in vascular lesions) and 42 (Αβ1-42, mainly found in AD-associated brain lesions), as well as the intracellular domain of APP (Figure 2).

Several factors, including aging, inflammation, renal dysfunction, ischemia, polymorphisms, and drugs, increase circulating levels and subsequent tissue deposition of Αβ by augmenting APP production and processing or by decreasing Αβ clearance and degradation (Figure 2, Online Tables 1 to 3).

Under normal conditions an equilibrium exists between Aβ production and removal in various compartments inside or outside of the central nervous system (15). Deregulation of this equilibrium may lead to accumulation of Αβ1-40 in blood, vascular wall, and heart tissues, which has been associated with CVD.

Figure 2
Figure 2 – APP and Αβ Metabolism
Following (1) amyloid precursor protein (APP) gene transcription, (2) APP is cleaved in the nonamyloidogenic pathway (plasma membrane) by α- and γ- secretases or in the amyloidogenic pathway (endosomes) by β- and γ- secretases. The later pathway generates amyloid beta (Αβ) peptides that are released extracellularly. (3) Αβ accumulation in blood or tissues may result from enhanced production/cleavage or by (4) impaired degradation and/or (5) clearance. ACE = angiotensin converting enzyme; AICD = amyloid precursor protein intracellular domain; apoE = apolipoprotein E; HDL = high-density lipoprotein; IDE = insulin degrading enzyme; sAPP = soluble amyloid precursor protein.

Systemic Accumulation of Aβ and CVD

Peripheral vascular Aβ abundance

Although APP processing in different cell types gives rise preferentially to Αβ1-40 or -42 (16), it is not known what drives this differential final processing of the amyloidogenic pathway of APP. In cases of CAA, neuronal-derived Αβ (either Αβ1-40 or -42) fails to drain away from the leptomeningeal vessels, capillaries, and brain parenchyma (17).

This defective depletion leads to its accumulation in brain arterioles. Αβ deposits are observed in the tunica media in close proximity as well as inside of the smooth muscle cells and in the adventitia, avoiding endothelial cells even at higher degrees of CAA (18,19).

Because impairment of adventitial lymphatic capillaries in peripheral vessels also aggravates atherosclerosis, the role of lymphatic drainage in Aβ-related cardiovascular disease should be further explored.

In peripheral atherosclerotic lesions, Αβ deposits consist almost exclusively from the Αβ1-40 species (20). Using mass spectrometry, Aβ1-40 peptide was on average 100 times more abundant than Aβ1-42 in human aortic atherosclerotic plaques (21).

The 2-peptide-amino-acid-longer species Αβ1-42, being more hydrophobic and fibrillogenic, is the main amyloid peptide found in parenchymal lesions of AD; however, its “vascular” involvement is limited to deposits in pericapillary spaces and glia limitans, parenchymal brain vessels, and leptomeningeal vessels.

Yet, overexpression of Αβ1-42 promotes Αβ1-40 vascular depositions in the brain (22), and factors that alter the Αβ1-40/-42 ratio, such as human apolipoprotein E4 (23), favor amyloid deposits in the form of CAA compared with parenchymal plaques.

This differential tissue preference of Aβ species may be explained by the following observations:

1) using 3D models of cerebrovascular vessels, researchers have recently demonstrated that HDL and apolipoprotein E (ApoE) synergistically promote vascular clearance of Aβ1-42 more than that of Aβ1-40 (24);

2) Αβ1-40 is produced in significant amounts from platelets, plaque invading macrophages (25), endothelial cells (26), and vascular smooth muscle cells (27); and

3) different ApoE isoforms, which are proteins with an impact in cholesterol transport system, seem to differentially regulate Aβ production, aggregation, and clearance (28).

More specifically, ApoE4 may inhibit Aβ clearance by competitively binding to the low-density lipoprotein receptor-related protein 1, and its presence has been associated with brain Αβ accumulation and increased AD risk. Interestingly, ApoE seems to affect also Αβ kinetics in blood (29).

Aβ and subclinical vascular disease

Aβ1-40 is critically involved in vascular aging. SIRT1, a class III histone deacetylase, plays a pivotal protective role in vascular aging (30) as it up-regulates α-secretase activity shifting Aβ metabolism towards the non-amyloidogenic pathway (Figure 2).

However, activation of the amyloidogenic pathway results in impairment of the vasodilating properties of small arterioles by enhancement of endothelin-1 expression (31), reduction of eNOS activity and endothelium-dependent vasodilation, enhancement of oxidative stress (32), and increased responsiveness to vasoconstrictors (33) (Table 1, Figure 3).

Further, Aβ oligomers may inhibit telomerase activity leading to telomere shortening (34), which actively promotes vascular aging. This experimental evidence generates the hypothesis that increased Aβ systemic concentrations may be associated with measurable, accelerated arterial aging and deteriorated vascular function and structure in humans.

Arterial pulse wave velocity is a well-established, noninvasive marker of arterial stiffness and vascular aging (35). Interestingly, the severity of cerebral β-amyloid deposition measured by positron emission tomography scan and its change over 2-year follow-up was associated with higher pulse wave velocity in nondemented elderly adults (36,37).

To assess whether Aβ1-40 is involved in early processes of arterial disease and aging, we prospectively examined changes in pulse wave velocity and plasma Aβ1-40 in 107 young to middle-aged healthy adults (mean age 46.2 years), clinically followed for 5 years (38). We found that the 5-year change of plasma Aβ1-40 levels was an independent determinant of the 5-year change in aortic stiffness.

Because Aβ1-40 deposits have been found in carotid human atherosclerotic plaques (25,39) and aortas (21), we examined whether plasma Aβ1-40 levels are associated with subclinical atherosclerosis in a population of 394 individuals with a wide range of CVD risk profiles.

After adjustment for age, traditional CVD risk factors, and renal function, increased Αβ1-40 was independently associated with higher carotid intima-media thickness, lower ankle-brachial index, and the severity and extent of arterial damage assessed in the carotid and femoral arteries, aorta, and coronary circulation (38).

Plasma Aβ1-40 was also associated with the severity of coronary artery calcium score in a sample of 3,266 adults from the Dallas Heart Study without clinically overt CVD (40).

Figure 3
Figure 3 – Detrimental Cellular and Molecular Effects of Aβ1-40 in the Cardiovascular System

Excess in blood Αβ1-40 levels exerts detrimental effects in vascular and blood cells promoting endothelial activation, atherosclerosis, and atherothrombosis. IL = interleukin; iNOS = inducible isoform of nitric oxide synthases; LDL = low-density lipoprotein; MCP = monocyte chemoattractant protein; NO = nitric oxide; ROS = reactive oxygen species; TNF = tumor necrosis factor; VCAM = vascular cell adhesion molecule; VSMC = vascular smooth muscle cells.

Table 1 – Role of APP and Aβ in Cardiovascular Biology and Disease

MoleculeStudy DesignTissue or Cell-Specific EffectsRef. #
Endothelial Cells
APPMurine and human cell lineIncreased protein levels of proinflammatory mediators (COX-2, VCAM-1) and increased secretion of IL-1β and Aβ1-40 through Src kinase signaling pathway(69)
Aβ1–40Human cell lineIncreased expression of inflammatory genes (MCP-1, GRO, ΙL-1β, and IL-6) through JNK-AP1 signaling pathway(48,70)
Aβ1–40Rat cell lineIncrease of endoplasmic reticulum stress through unfolded protein response(71)
Aβ1–40Human, mouse, rat, and bovine cell lineInhibition of the KCa2+ channel opening and reduced Ca2+ efflux(71,72)
Aβ1–40Human and rat cell lineActivation of caspase-dependent and -independent apoptosis through caspase 12 and cytochrome c(48,71)
Aβ1–40
Aβ1–42
Aβ25–35
Human, mouse, bovine, and porcine cell line, rat arteriesInhibition of NO signaling in a concentration-manner through interaction with CD36(72,73)
Aβ1–40
Aβ1–42
Human cell lineSignature transcriptomic of essential endothelial function affected(48)
Smooth Muscle Cells
Aβ1–42Human and porcine cell lineDecrease in sGC activity and cGMP production(73)
Cardiomyocytes
Aβ1–40
Aβ1–42
Murine and human cell lineDecrease of cell viability(48)
Monocytes
APPMurine and human cell lineRecruitment of tyrosine kinases Lyn and Syk to APP during β1 integrin-mediated adhesion of monocyte through tyrosine kinase mechanism(69,74,75)
Aβ1–42Human monocytesDifferentiation of monocytes into macrophages(76)
Aβ1–40
Aβ1–42
Aβ25–35
Human monocytes
Human cell line
Hypersecretion of inflammatory cytokines (TNF-α and IL-1β) and chemokines (MCP-1, IL-8, MIP-1 α, and CCR5) through activation of ERK-1/-2(43,76-79)
Aβ1–40
Aβ1–42
Aβ25–35
Human and murine cell lineSecretion of ROS(79)
Aβ1-40Human cell lineMigration of monocyte through ERK-1/-2 and RAGE receptor(74,80)
Aβ1-40
Aβ1-42
Human cellOpsonization of lipoproteins enhances their uptake by human monocytes, resulting in cholesterol accumulation(81)
Macrophages
Aβ1–40Murine cell lineEnhanced nitrite production in the presence of IFN-γ macrophage activation(25)
Aβ1-40
Aβ1-42
Human cellOpsonization of lipoproteins enhances their uptake by macrophages, resulting in cholesterol accumulation
Accelerated formation of foam cells
(81)
Aβ1–42Macrophages from CD36−/− miceProduction of ROS and proinflammatory cytokines IL-1β and TNF-α through CD36 signaling(82,83)
Platelets
sAPP695α
sAPP751α
sAPP770α
Human plateletInhibition of platelet aggregation and secretion(84)
Aβ1–40Amyloid properties induced in unrelated proteins to stimulate human and murine plateletsPlatelet aggregation through either a CD36-p38MAPK-TXA2 or a glycoprotein Ibα pathway(85)
Aβ1–40
Aβ25–35
Human plateletPlatelet aggregation with Ca2+ mobilization and PLC γ 2-PKC pathway activation(86)
Aβ25–35Human and murine plateletPlatelet activation through RhoA-dependent modulation of actomyosin
Increase in intracellular Ca2+, leading to dense granule release and ADP secretion
(87,88)
Aβ1–40
Aβ1–42
Aβ25–35
Human and murine plateletPlatelet adhesion and spreading through the elongation of filopodia and lamellipodia(89,90)
Aβ1-42Human plasmaThrombin generation in an FXII-dependent FXI activation(91)
Aβ1–40Human and murine plateletROS generation and cell shrinkage(89)
APPOverexpression of human APP isoform 770 in mice plateletsMarked inhibition of thrombosis in vivo(85)
APPOverexpression of human APP isoform 751 in miceProthrombotic phenotype in vivo(61)

APP = amyloid precursor protein; Aβ = amyloid beta; CCR5 = chemokine receptor type 5; cGMP = cyclic guanosine monophosphate; COX = cyclooxygenase; ERK = extracellular signal–regulated kinase; FX = coagulation factor.; GRO = growth-related oncogene; IL = interleukin; IFN = interferon; JNK-AP = c-Jun N-terminal kinase–activator protein; MCP = monocyte chemo-attractant protein; MIP = macrophage inflammatory protein; NO = nitric oxide; PKC = protein kinase C; PLC = phospholipase C; RAGE = receptor advanced glycation end products; ROS = reactive oxygen species; sGC = soluble guanylyl cyclase; TNF = tumor necrosis factor; TXA2 = thromboxane A2; VCAM = vascular cell adhesion molecule.

Overall, these findings are indicative of direct and indirect roles of Aβ1-40 in accelerated arterial aging, atherosclerosis at various stages, and vascular beds, taking place long before the establishment of clinically overt CVD.

Αβ1-40 in coronary artery disease

Circulating Aβ1-40 levels were independently associated with the presence of angiographically documented stable coronary artery disease (CAD) in 2 independent cohorts consisting of 514 and 396 patients (38). This association was confirmed in subsequent studies, including adults with normal cognitive function or patients with AD (41,42).

Experimental evidence indicates that Aβ peptides may be actively involved in downstream pathways leading to plaque rupture, thrombosis, and subsequent clinical manifestations of the acute coronary syndrome (ACS) (Figure 3).

Αβ1-40 stimulates platelet activation and adhesion in humans and mice (Table 1) and induces release of matrix metalloproteinases by human monocytes to increase plaque vulnerability (43).

Interestingly, in a myocardial infarction rat model, early surges in plasma sAPP770 concentrations preceded the release of cardiac injury enzymes (26), while plasma sAPP was also increased in patients with ACS (26), suggesting that enhanced APP/Aβ processing and subsequent release of sAPP770 and Αβ1-40 may trigger plaque rupture or its sequalae in ACS.

In support of this hypothesis (Figure 3), we recently reported that in 2 independent cohorts of patients with non-ST-segment elevation ACS, higher blood Aβ1-40 levels were associated with worse risk profile, including a higher GRACE (Global Registry of Acute Coronary Events) score high sensitivity cardiac troponin T and lower systolic blood pressure and estimated glomerular filtration rate (44), implying a concentration-dependent relation of Aβ with the severity of ACS.

Overall, the results of these studies provide conceptual proof that Aβ metabolism is enhanced in CAD and Aβ1-40 levels in blood are increased and associated with its clinical presentation.

Αβ1-40 in coronary artery disease

Circulating Aβ1-40 levels were independently associated with the presence of angiographically documented stable coronary artery disease (CAD) in 2 independent cohorts consisting of 514 and 396 patients (38). This association was confirmed in subsequent studies, including adults with normal cognitive function or patients with AD (41,42).

Experimental evidence indicates that Aβ peptides may be actively involved in downstream pathways leading to plaque rupture, thrombosis, and subsequent clinical manifestations of the acute coronary syndrome (ACS) (Figure 3).

Αβ1-40 stimulates platelet activation and adhesion in humans and mice (Table 1) and induces release of matrix metalloproteinases by human monocytes to increase plaque vulnerability (43).

Interestingly, in a myocardial infarction rat model, early surges in plasma sAPP770 concentrations preceded the release of cardiac injury enzymes (26), while plasma sAPP was also increased in patients with ACS (26), suggesting that enhanced APP/Aβ processing and subsequent release of sAPP770 and Αβ1-40 may trigger plaque rupture or its sequalae in ACS.

In support of this hypothesis (Figure 3), we recently reported that in 2 independent cohorts of patients with non-ST-segment elevation ACS, higher blood Aβ1-40 levels were associated with worse risk profile, including a higher GRACE (Global Registry of Acute Coronary Events) score high sensitivity cardiac troponin T and lower systolic blood pressure and estimated glomerular filtration rate (44), implying a concentration-dependent relation of Aβ with the severity of ACS.

Overall, the results of these studies provide conceptual proof that Aβ metabolism is enhanced in CAD and Aβ1-40 levels in blood are increased and associated with its clinical presentation.

Reference : link


More information: Junpei Takahashi et al, Oxytocin reverses Aβ-induced impairment of hippocampal synaptic plasticity in mice, Biochemical and Biophysical Research Communications (2020). DOI: 10.1016/j.bbrc.2020.04.046

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