Muscle tissue changes with aging

Muscle tissue changes with aging


Purpose of review

This review article focuses on the changes that occur in muscle with age, specifically the involuntary loss of muscle mass, strength and function, termed sarcopenia. Particular emphasis is given to the metabolic alterations that characterize sarcopenia, and to the potentially treatable causes of this condition, including age-related endocrine and nutritional changes, and inactivity.

Recent findings

Recent data reported include those regarding the potential role of insulin resistance in the development of sarcopenia, the potential role of androgens and growth hormone in the treatment of this condition, the usefulness of exercise including both resistance and aerobic training to improve muscle growth and function, and, finally, the possible use of nutritional manipulations to improve muscle mass.


Sarcopenia is likely a multifactorial condition that impairs physical function and predisposes to disability. It may be prevented or treated with lifestyle interventions and pharmacological treatment. Further long-term investigations are needed, however, to ascertain what type and combinations of interventions are the most efficacious in improving muscle mass and function in older people.


One of the most striking effects of age is the involuntary loss of muscle mass, strength, and function, termed sarcopenia [13]. Muscle mass decreases approximately 3–8% per decade after the age of 30 and this rate of decline is even higher after the age of 60 [4,5]. This involuntary loss of muscle mass, strength, and function is a fundamental cause of and contributor to disability in older people. This is because sarcopenia increases the risks of falls and vulnerability to injury and, consequently, can lead to functional dependence and disability [6,7]. A decrease in muscle mass is also accompanied by a progressive increase in fat mass and consequently changes in body composition, and is associated with an increased incidence of insulin resistance in the elderly [1,4,5,8]. Furthermore, bone density decreases, joint stiffness increases, and there is a small reduction in stature (kyphosis). All these changes have probable implications for several conditions, including type 2 diabetes, obesity, heart disease, and osteoporosis.

Potential causes of sarcopenia

The etiology of sarcopenia is not clearly understood, but several mechanisms have been proposed. At the cellular level, specific age-related alterations include a reduction in muscle cell number, muscle twitch time and twitch force, sarcoplasmic reticulum volume and calcium pumping capacity [2,9]. Sarcomere spacing becomes disorganized, muscle nuclei become centralized along the muscle fiber, the plasma membrane of muscle becomes less excitable, and there is a significant increase in fat accumulation within and around the muscle cells. Neuromuscular alterations include a decrease in the nervous firing rate to muscle, the number of motor neurons, and the regenerative abilities of the nervous tissue. Motor unit size also increases [2]. Further, aging is associated with changes in satellite cell number and recruitment, an indication and potential cause of reduced muscle growth [1012].

Biochemical and metabolic changes also occur in muscle with aging. Mitochondrial DNA deletion mutations subsequent to oxidative damage and reduced mitochondrial protein synthesis have been reported and are probably linked with a reduction in glycolytic and oxidative enzyme activities, creatine phosphate and ATP stores within the muscle cell, mitochondrial volume, and a slight reduction in overall metabolic rate (~10%) [1316]. These metabolic changes in muscle contribute to the overall physical fitness capacity of the elderly and are an important component of the reduction of around 30% in the ability to utilize oxygen during exercise (i.e. VO2max).

Initial studies on a small number of elderly people have also suggested that aging is associated with a reduction in the basal muscle protein synthesis, which might have been responsible for the progressive reduction in muscle mass [1721]. More recent data obtained in the largest cohort of healthy older men, however, did not confirm the earlier reports and concluded that differences in basal muscle protein turnover between elderly and young men cannot explain muscle loss with age, suggesting that future research should focus on responses to specific stimuli, such as nutrition, exercise, or disease [22].

Besides the muscle-specific alterations highlighted above, other age-related changes in endocrine function or responsiveness to hormonal stimuli, nutrition or responsiveness to nutrients, and physical activity may be responsible for the development and worsening of sarcopenia [2330]. Most likely, sarcopenia is a multifactorial problem. Among all its potential causes, however, a reduction in endocrine function, physical activity and appropriate nutrition are potentially treatable with behavioral interventions or pharmacological agents, and for this reason will be discussed in this review.

Endocrine changes relevant to sarcopenia

A variety of hormonal changes are seen during the aging process that may contribute to muscle loss with aging. We have selected the most important changes in relation to their effect on skeletal muscle.

The primary and most potent anabolic steroid is testosterone. In about 60% of men over the age of 65, testosterone levels decrease to below the normal youthful values, in a process termed andropause [31]. Unlike the rapid decrease in estradiol seen with menopause, testosterone concentrations gradually decrease throughout the aging process [31]. Since testosterone increases muscle protein synthesis, muscle mass and strength [32,33], it has been proposed that the decrease in testosterone may cause a decrease in muscle protein synthesis and result in a loss of muscle mass. With this in mind, several studies have examined the effect of testosterone replacement therapy in men with overt hypogonadism or testosterone concentrations at the lower-normal range. Testosterone was administered via injection, transdermal patch, or dermal gel [24,3438]. From these studies it was shown that testosterone replacement to mid-normal levels resulted in a significant increase in muscle mass, muscle strength, muscle protein synthesis and bone density. These results thus suggest that andropause may be a player in the development of sarcopenia, and highlight that testosterone therapy may lead to a reversal or attenuation of sarcopenia. Testosterone is currently not recommended for the treatment of sarcopenia, however, and a careful evaluation of the potential benefits and potential risks (e.g. increased prostate-specific antigen, hematocrit and cardiovascular risk) should be performed before making such a recommendation [39].

In women, estradiol levels abruptly decrease during menopause [31]. Very little information is available regarding the role of menopause in sarcopenia. It appears that muscle mass is not affected by the decrease in estrogens. Cross-sectional studies evaluating the effects of age on lean body mass and appendicular muscle mass have shown that the rate of decline of muscle mass in women does not increase after menopause, suggesting a marginal role, if any, of this event in the development of sarcopenia in women [5]. Hormone replacement therapy, however, can significantly increase serum steroid hormone binding globulin, which leads to a significant decrease in serum free testosterone levels in women [40]. Low serum free testosterone levels in women are associated with a lower muscle mass. Therefore, hormone replacement therapy may play a role in further reducing, rather than increasing, muscle mass in older women.

The growth hormone/insulin-like growth factor-I axis also exhibits a gradual decline during normal aging [31]. Although providing growth hormone replacement therapy to growth hormone deficient adults resulted in an increase in muscle mass, some studies have shown no effect on muscle strength [4146]. Growth hormone replacement therapy in the elderly appears to be beneficial for lowering fat mass, improving blood lipid profiles and increasing lean body mass, but these changes may not lead to an increase in muscle strength and function. In fact, muscle strength only increased when growth hormone was given to elderly men undergoing a weight-training program as compared with growth hormone replacement therapy alone, or when sex hormone replacement therapy was given in conjunction with growth hormone [41,46]. It is also important to underscore that the methodologies used to measure body composition may be affected by water retention. Thus, an increase in muscle mass with a reduction of fat mass with no change in strength following growth hormone therapy should be interpreted with caution because growth hormone notoriously increases water retention, which can be misinterpreted as an increase in lean body mass. As for testosterone, growth hormone replacement is not currently recommended for the treatment of sarcopenia due to both the results of the published studies and the potentially serious side effects (arthralgia, edema, insulin resistance, cardiovascular risk, etc.) [41].

The concentrations of dehydroepiandrosterone in the blood also decrease gradually with normal aging (adrenopause) [31]. In fact, levels may be up to five times lower in very old men as compared with younger men. Oral supplementation of dehydroepiandrosterone in older persons does restore levels to youthful values, increases insulin-like growth factor-I levels in men and women, increases estrogens in men, and increases testosterone in women [4750]. However, no changes in lean body mass were detected and HDL-cholesterol levels significantly decreased [47,49]. Nonetheless, muscle strength was increased in older men (but not women) undergoing dehydroepiandrosterone supplementation in one particular study [48]. Recently, a very large study in older individuals showed that dehydroepiandrosterone replacement therapy has no effect on muscle size, strength or function [50]. Thus, the importance of adrenopause in the development of sarcopenia remains to be demonstrated.

The ability of muscle tissue to respond to insulin is an important aspect of overall insulin sensitivity. The incidences of insulin resistance and type 2 diabetes increase with aging and sarcopenia may play an important role. Most studies have reported that the prevalence of insulin resistance and glucose intolerance is higher in older individuals when the data are reported per unit of body mass, but these differences disappear if the data are corrected by lean body mass [5155]. This suggests that the changes in body composition may drive the increase in insulin resistance with age. Although insulin is usually considered in the context of its ability to increase glucose uptake into cells, there is emerging evidence that insulin resistance of muscle and whole body protein metabolism in the elderly may be an important contributor to sarcopenia [29,56]. For example, when glucose is ingested with a regular meal, the subsequent increase in insulin concentrations has a negative effect on muscle protein synthesis only in older individuals [29]. This implies that with normal aging the ability of muscle cells to properly respond to circulating insulin (by increasing muscle protein synthesis) is impaired.

Physical activity and sarcopenia

Another important contributor to sarcopenia is inactivity. Although it is difficult to causally determine the relative importance of a sedentary lifestyle in the development of sarcopenia, it is very well known that short-term muscle inactivity severely reduces muscle mass and strength even in young individuals. Typical examples are bed rest and weightlessness [57,58]. It is also recognized that these muscle changes can be counteracted by exercise, typically resistance exercise [59]. Several authors have reported that acute resistance exercise increases myofibrillar muscle protein synthesis both in young and older adults [20,21]. Progressive resistance exercise training has also been shown to induce muscle hypertrophy and increase strength in elderly and physically frail adults [12,19,6066]. Despite the clear efficacy in increasing muscle mass, strength and function, however, resistance exercise training may be a difficult intervention to implement in community-indwelling older individuals due to the necessity of specific equipment and supervision, the possibility that it may not be indicated in certain conditions frequently found in older patients (e.g. hypertension, stroke), and the fact that weight lifting may not be an appealing activity for sedentary elders.

Aerobic exercise has been shown in several studies to improve VO2max, mitochondrial density and activity, insulin sensitivity and energy expenditure in young and older individuals [6769]. Two studies have also shown that prolonged and intense aerobic exercise can increase muscle protein synthesis in young active individuals [7071]. Recent preliminary data suggest that aerobicexercise (40% VO2max) can also acutely increase muscle protein synthesis in healthy, independent older people [72]. Although aerobic exercise does not induce obvious muscle hypertrophy, some studies have shown that intense aerobic exercise training can induce some degree of hypertrophy, as indicated by increased calf circumference, muscle fiber area, and satellite cell activation [73,74]. The characteristic physique of marathon runners, the epitome of aerobic exercisers, may cast doubts about the anabolic efficacy on aerobic exercise. It is important to underscore, however, that the muscles of these athletes, although not hypertrophic, do not lack strength and power as do the muscles of sarcopenic older adults. In fact, muscle mass is not the only determinant of muscle function, and aerobic exercise training may have important positive effects on neuromuscular adaptations and, consequently, muscle quality especially in individuals who were sedentary and sarcopenic prior to the exercise intervention. In fact, muscle quality has been shown to improve significantly with resistance training in older people and in younger people with muscle wasting [75,76].

Thus, both resistance and aerobic exercise can be very useful to counteract sarcopenia and the associated metabolic alterations of the muscle.

Nutrition and sarcopenia

Malnutrition leads to muscle wasting. It has been shown that aging is associated with a progressive reduction in food intake, which predisposes to energy-protein malnutrition [30]. Further, older people may voluntarily reduce their protein intake in order to comply with reduced fat and cholesterol diets. Recent studies [77] suggest that the protein requirements of older individuals may be higher (~1 g/kg/day) than the level currently recommended by the Institute of Medicine (0.8 g/kg/day) [78]. Thus, nutritional interventions are appealing potential means for the prevention and treatment of sarcopenia of the elderly due to the easy applicability and safety. Amino acids from ingested protein directly stimulate muscle protein synthesis [79]. Interestingly, healthy elderly individuals respond to an amino acid stimulus with an increase in muscle protein synthesis that is not significantly different from the effect observed in their younger counterparts [8082]. However, attempts to increase muscle mass, strength, and muscle protein synthesis with commercial nutritional supplements or high-protein diets have been largely unsuccessful [83,84]. Although an earlier and smaller study reported increases in muscle mass with nutritional supplementation [85], in a much larger cohort of frail elderly individuals, Fiatarone et al. [60] reported increases in muscle mass and strength associated with resistance exercise but not with nutritional supplementation. Furthermore, nutritional supplementation or high-protein meals added to resistance exercise did not result in an increase in muscle mass, strength, or muscle protein synthesis as compared with exercise alone [60,83,84]. There are at least two possible explanations for the inability of nutritional supplements or increased protein intake to enhance muscle growth and strength. First, the presence of carbohydrate in a nutritional supplement for the elderly is not beneficial [29], and may in fact impair the anabolic response of muscle proteins to the positive effect of amino acids alone [80,81]. These data are consistent with findings in old rats, indicating that muscle protein synthesis is blunted during balanced feeding [28]. Because both the commercial supplements and the high-protein diets previously tested in older adults contained carbohydrate, this alone might provide a sufficient explanation as to the ineffectiveness of those interventions [60,83,84]. Second, it has been reported that older adults who were given supplements in the absence of increases in physical activity decreased their dietary intake, so that their total daily energy intake remained unchanged [60]. This indicates that nutritional supplements for the elderly would be better considered as dietary substitutes. Consequently, if the nutrient content of the supplement is little different from that of the normal diet, it is likely that the supplementation will be ineffective. Hence, a nutritional supplement for the prevention or treatment of sarcopenia should only contain the nutrients that are absolutely necessary for the stimulation of muscle protein anabolism, in order to achieve the highest anabolic efficiency (anabolic effect per unit of energy). Data from young adults suggest that essential amino acids are mostly responsible for the amino acid-induced stimulation of muscle protein synthesis [86,87], whereas nonessential amino acids do not appear to exert any significant effect even when given at very high doses [87]. Recent studies show that this is also true for older people. In fact, essential amino acids are primarily responsible for the amino acid stimulation of muscle protein anabolism in healthy elderly individuals, whereas nonessential amino acids are apparently not required [82]. Specifically, the intake of 18 g of essential amino acids alone or in combination with 22 g of nonessential amino acids increased net muscle protein anabolism. The magnitude of the anabolic effect of both supplements was similar. It is important to consider, however, that whereas the essential amino acid content and composition of both supplements was identical, the balanced amino acid supplement delivered more than twice as much energy and amino-nitrogen as the essential amino acid supplement.

Nonessential amino acids comprise a significant portion of dietary proteins, including the high-quality proteins (e.g. whey, egg) that are typically used to supplement protein-poor diets. Since nonessential amino acids do not appear to be necessary for the acute stimulation of muscle protein anabolism in older people, high-quality proteins may still be inadequate for a dose-effective prolonged treatment of sarcopenia, given the excessive amount of calories that they provide in the form of nonessential amino acids. Thus, the elimination of any source of energy that does not stimulate protein anabolism, including nonessential amino acids and carbohydrate, should not decrease the long-term anabolic effect of the essential amino acid supplement for the elderly, while significantly decreasing its total caloric content. However, there are no data regarding the efficacy of prolonged supplementation with a highly efficient mixture of essential amino acids on muscle growth in the elderly. Therefore, long-term randomized clinical trials are necessary to clearly assess whether highly efficient nutritional supplements can effectively improve muscle mass in sarcopenic older individuals.


Sarcopenia is a multifactorial process. A reduction in endocrine function, physical activity and inadequate nutrition all play an important role in the reduction of muscle mass with normal aging. Testosterone replacement therapy could be a useful intervention in hypogonadal older men for increasing muscle mass and strength, although it is not currently recommended. Hormone replacement therapy for menopause, adrenopause or somatopause appears to have a marginal or no positive effect on muscle mass and strength. Exercise training and proper nutrition can have dramatic effects on muscle mass and strength. An optimal intervention program may include an exercise-training schedule that incorporates both resistance and aerobic exercise with adequate intake of total calories and protein. This would not only improve muscle mass and strength, but it would also reduce insulin resistance, which is more prevalent in the elderly. Providing a nutritional supplement of only amino acids or protein might also be beneficial to promote muscle growth by stimulating muscle protein synthesis and increasing the total daily caloric intake, but further investigations are needed.

Fortunately, aged muscle is still very plastic and can respond to anabolic stimuli by increasing its mass and strength. This knowledge is vital for designing interventions to reverse or attenuate the loss of muscle mass with aging and to improve functional abilities in the elderly.


This work was funded in part by the National Institute on Aging/NIH grant #AG18311.

Overcome Erectile Dysfunction for better health and a better sex life

Whether you currently suffer from ED or are hoping to sidestep this condition, try these tips to overcome ED for better health and a better sex life.

  1. Start walking. According to one Harvard study, just 30 minutes of walking a day was linked with a 41% drop in risk for ED. Other research suggests that moderate exercise can help restore sexual performance in obese middle-aged men with ED.
  2. Eat right. In the Massachusetts Male Aging Study, eating a diet rich in natural foods like fruit, vegetables, whole grains, and fish — with fewer red and processed meat and refined grains — decreased the likelihood of ED.
  3. Pay attention to your vascular health. High blood pressure, high blood sugar, high cholesterol, and high triglycerides can all damage arteries in the heart (causing heart attack), in the brain (causing stroke), and leading to the penis (causing ED). An expanding waistline also contributes. Check with your doctor to find out whether your vascular system — and thus your heart, brain, and penis — is in good shape or needs a tune-up through lifestyle changes and, if necessary, medications.
  4. Size matters, so get slim and stay slim. A trim waistline is one good defense — a man with a 42-inch waist is 50% more likely to have ED than one with a 32-inch waist. Losing weight can help fight erectile dysfunction, so getting to a healthy weight and staying there is another good strategy for avoiding or fixing ED. Obesity raises risks for vascular disease and diabetes, two major causes of ED. And excess fat interferes with several hormones that may be part of the problem as well.
  5. Move a muscle, but we’re not talking about your biceps. A strong pelvic floor enhances rigidity during erections and helps keep blood from leaving the penis by pressing on a key vein. In a British trial, three months of twice-daily sets of Kegel exercises (which strengthen these muscles), combined with biofeedback and advice on lifestyle changes — quitting smoking, losing weight, limiting alcohol — worked far better than just advice on lifestyle changes.

For more on diagnosing, treating, and learning how to overcome ED, buy Erectile Dysfunction, a Special Health Report from Harvard Medical School.

Papaya Leaf Extract renews muscle tissue

As alternative medicine grows in popularity, people are beginning to search everywhere for natural, health-promoting foods and supplements. It seems apparent that organic food rises far above conventional in helping to maintain a healthy body, but even organic food is highly depleted in nutrients compared to decades ago. There is little way around natural supplementation today, as soil is depleted and mainstream vitamins provide little or no benefit. People can utilize the health benefits of turmeric, vitamin D, and cacao, but there are other very powerful supplements out there that will contribute to incredible health.

Papaya Leaf Extract a Powerful Health Booster

One supplement you should not overlook is Papaya Leaf Extract. Papayas are excellent sources of dietary fiber, vitamin C, vitamin A, vitamin E, and folate, while at the same time being rich in antioxidants, flavonoids, and carotenes. Papayas also contain high amounts of enzymes called papain and chymopapain, which are critical ingredients for a healthy body. Enzymes are responsible for almost every aspect of life and health, and are needed to help control all mental and physical functions.

So what are the real uses for papaya leaf extract ? The beneficial properties surrounding papaya have been known for generations, but they are now just gaining back some attention. Some of the healing properties papayas provide are:

  • Increased quality of proteins in whole organism.
  • Revitalization of the human body and a maintaining of energy and vitality.
  • Encouraged renewal of muscle tissue.
  • Supported cardiovascular system.
  • Strengthened immune system
  • Help with the digestive system by breaking down proteins and supporting production of digestive enzymes.
  • Treatment for skin wounds that don’t heal quickly.
  • Prevention of cataract formation.
  • Lowered risk of emphysema in smokers and passive smokers thanks to high vitamin D content.
  • Alleviated inflammation.
  • Help with nausea and constipation.
  • Fighting various cancers and aiding the cardiovascular and gastrointestinal systems.
Although papaya leaf extract is often viewed as an excellent treatment for digestive disorders as well as disturbances of the gastrointestinal tract, it provides many more health benefits than just that (as outlined above). The papain enzyme found in papaya has also been utilized around the world to eliminate parasites within the body.


How to attain healthy blood and muscles to prevent Alzheimer’s ?

How to attain healthy blood and muscles to prevent Alzheimer’s ?

Adequate sleep

During sleep, our body is detoxing. Many of my cancer and Alzheimer’s clients do not sleep well at night.

Adequate sunshine or Vitamin D

Many of those with Alzheimer’s do not exercise often and are not taking Vitamin D.

Normal blood sugar

Their blood tests shows high levels of blood sugar.

Stronger immune system

Search this site for immune system, lymphatic, massage , Vitamin D, blood, ketogenic diet, restricted calorie diet, inflammation, toxins and sleep

Quality supplementation for stronger blood vessels

Nutrients that are important to have strong blood vessels include Vitamin D, C, E, A, B complex, sufur rich foods (e.g., onions, garlic) and probiotics. Visit this site to try these supplements (Lifepak and AGELOC family of products ) at:


Connie Dello Buono


Alzheimer’s Disease Might Be a ‘Whole Body’ Problem

Summary: Using a technique called parabiosis on pairs of mice, researchers discover what they call ‘cancer like mobility’ of amyloid beta, reporting it can travel to the brain from other parts of the body.

Source: University of British Columbia.

Alzheimer’s disease, the leading cause of dementia, has long been assumed to originate in the brain. But research from the University of British Columbia and Chinese scientists indicates that it could be triggered by breakdowns elsewhere in the body.

The findings, published today in Molecular Psychiatry, offer hope that future drug therapies might be able to stop or slow the disease without acting directly on the brain, which is a complex, sensitive and often hard-to-reach target. Instead, such drugs could target the kidney or liver, ridding the blood of a toxic protein before it ever reaches the brain.

The scientists demonstrated this cancer-like mobility through a technique called parabiosis: surgically attaching two specimens together so they share the same blood supply for several months.

UBC Psychiatry Professor Dr. Weihong Song and Neurology Professor Yan-Jiang Wang at Third Military Medical University in Chongqing attached normal mice, which don’t naturally develop Alzheimer’s disease, to mice modified to carry a mutant human gene that produces high levels of a protein called amyloid-beta. In people with Alzheimer’s disease, that protein ultimately forms clumps, or “plaques,” that smother brain cells.

Normal mice that had been joined to genetically modified partners for a year “contracted” Alzheimer’s disease. Song says the amyloid-beta traveled from the genetically-modified mice to the brains of their normal partners, where it accumulated and began to inflict damage.

Not only did the normal mice develop plaques, but also a pathology similar to “tangles” – twisted protein strands that form inside brain cells, disrupting their function and eventually killing them from the inside-out.

Other signs of Alzheimer’s-like damage included brain cell degeneration, inflammation and microbleeds.

In addition, the ability to transmit electrical signals involved in learning and memory – a sign of a healthy brain – was impaired, even in mice that had been joined for just four months.


Besides the brain, amyloid-beta is produced in blood platelets, blood vessels and muscles, and its precursor protein is found in several other organs.

But until these experiments, it was unclear if amyloid-beta from outside the brain could contribute to Alzheimer’s disease. This study, Song says, shows it can.

“The blood-brain barrier weakens as we age,” says Song, a Canada Research Chair in Alzheimer’s Disease and the Jack Brown and Family Professor. “That might allow more amyloid beta to infiltrate the brain, supplementing what is produced by the brain itself and accelerating the deterioration.”

Song, head of UBC’s Townsend Family Laboratories, envisions a drug that would bind to amyloid-beta throughout the body, tagging it biochemically in such a way that the liver or kidneys could clear it.

“Alzheimer’s disease is clearly a disease of the brain, but we need to pay attention to the whole body to understand where it comes from, and how to stop it,” he says.


Source: Brian Kladko – University of British Columbia
Publisher: Organized by
Image Source: image is credited to University of British Columbia.
Original Research:Abstract for “Blood-derived amyloid-β protein induces Alzheimer’s disease pathologies” by X-L Bu, Y Xiang, W-S Jin, J Wang, L-L Shen, Z-L Huang, K Zhang, Y-H Liu, F Zeng, J-H Liu, H-L Sun, Z-Q Zhuang, S-H Chen, X-Q Yao, B Giunta, Y-C Shan, J Tan, X-W Chen, Z-F Dong, H-D Zhou, X-F Zhou, W Song and Y-J Wang in Molecular Psychiatry. Published online October 31 2017 doi:10.1038/mp.2017.204

University of British Columbia “Alzheimer’s Disease Might Be a ‘Whole Body’ Problem.” NeuroscienceNews. NeuroscienceNews, 31 October 2017.


Blood-derived amyloid-β protein induces Alzheimer’s disease pathologies

The amyloid-β protein (Aβ) protein plays a pivotal role in the pathogenesis of Alzheimer’s disease (AD). It is believed that Aβ deposited in the brain originates from the brain tissue itself. However, Aβ is generated in both brain and peripheral tissues. Whether circulating Aβ contributes to brain AD-type pathologies remains largely unknown. In this study, using a model of parabiosis between APPswe/PS1dE9 transgenic AD mice and their wild-type littermates, we observed that the human Aβ originated from transgenic AD model mice entered the circulation and accumulated in the brains of wild-type mice, and formed cerebral amyloid angiopathy and Aβ plaques after a 12-month period of parabiosis.

AD-type pathologies related to the Aβ accumulation including tau hyperphosphorylation, neurodegeneration, neuroinflammation and microhemorrhage were found in the brains of the parabiotic wild-type mice. More importantly, hippocampal CA1 long-term potentiation was markedly impaired in parabiotic wild-type mice.

To the best of our knowledge, our study is the first to reveal that blood-derived Aβ can enter the brain, form the Aβ-related pathologies and induce functional deficits of neurons.

Our study provides novel insight into AD pathogenesis and provides evidence that supports the development of therapies for AD by targeting Aβ metabolism in both the brain and the periphery.

“Blood-derived amyloid-β protein induces Alzheimer’s disease pathologies” by X-L Bu, Y Xiang, W-S Jin, J Wang, L-L Shen, Z-L Huang, K Zhang, Y-H Liu, F Zeng, J-H Liu, H-L Sun, Z-Q Zhuang, S-H Chen, X-Q Yao, B Giunta, Y-C Shan, J Tan, X-W Chen, Z-F Dong, H-D Zhou, X-F Zhou, W Song and Y-J Wang in Molecular Psychiatry. Published online October 31 2017 doi:10.1038/mp.2017.204

From Wiki:

Normal function


The normal function of Aβ is not well understood.[7] Though some animal studies have shown that the absence of Aβ does not lead to any obvious loss of physiological function,[8][9] several potential activities have been discovered for Aβ, including activation of kinase enzymes,[10][11] protection against oxidative stress,[12][13]regulation of cholesterol transport,[14][15] functioning as a transcription factor,[16][17] and anti-microbial activity (potentially associated with Aβ’s pro-inflammatory activity).[18]

The glymphatic system clears metabolic waste from the mammalian brain, and in particular beta amyloids.[19] The rate of removal is significantly increased during sleep.[20] However, the significance of the glymphatic system in Aβ clearance in Alzheimer’s disease is unknown.[21]

Disease associations

Aβ is the main component of amyloid plaques (extracellular deposits found in the brains of patients with Alzheimer’s disease).[22] Similar plaques appear in some variants of Lewy body dementia and in inclusion body myositis (a muscle disease), while Aβ can also form the aggregates that coat cerebral blood vessels in cerebral amyloid angiopathy. The plaques are composed of a tangle of regularly ordered fibrillar aggregates called amyloid fibers,[23] a protein fold shared by other peptides such as the prions associated with protein misfolding diseases.

Brain Aβ is elevated in patients with sporadic Alzheimer’s disease. Aβ is the main constituent of brain parenchymal and vascular amyloid; it contributes to cerebrovascular lesions and is neurotoxic.[32][33][34][35] It is unresolved how Aβ accumulates in the central nervous system and subsequently initiates the disease of cells. Some researchers have found that the Aβ oligomers induce some of the symptoms of Alzheimer’s Disease by competing with insulin for binding sites on the insulin receptor, thus impairing glucose metabolism in the brain.[36] Significant efforts have been focused on the mechanisms responsible for Aβ production, including the proteolytic enzymes gamma- and β-secretases which generate Aβ from its precursor protein, APP (amyloid precursor protein).[37][38][39][40] Aβ circulates in plasma, cerebrospinal fluid (CSF) and brain interstitial fluid (ISF) mainly as soluble Aβ40[32][41] Senile plaques contain both Aβ40 and Aβ42,[42] while vascular amyloid is predominantly the shorter Aβ40. Several sequences of Aβ were found in both lesions.[43][44][45] Generation of Aβ in the CNS may take place in the neuronal axonal membranes after APP-mediated axonal transport of β-secretase and presenilin-1.[46]

Increases in either total Aβ levels or the relative concentration of both Aβ40 and Aβ42 (where the former is more concentrated in cerebrovascular plaques and the latter in neuritic plaques)[47] have been implicated in the pathogenesis of both familial and sporadic Alzheimer’s disease. Due to its more hydrophobic nature, the Aβ42 is the most amyloidogenic form of the peptide. However the central sequence KLVFFAE is known to form amyloid on its own, and probably forms the core of the fibril.[citation needed] One study further correlated Aβ42 levels in the brain not only with onset of Alzheimer’s, but also reduced cerebrospinal fluid pressure, suggesting that a build-up or inability to clear Aβ42 fragments may play a role into the pathology.[

Low-temperature and low-salt conditions allowed to isolate pentameric disc-shaped oligomers devoid of beta structure.[65] In contrast, soluble oligomers prepared in the presence of detergents seem to feature substantial beta sheet content with mixed parallel and antiparallel character, different from fibrils;[66] computational studies suggest an antiparallel beta-turn-beta motif instead for membrane-embedded oligomers.[67]

The suggested mechanisms by which amyloid beta may damage and cause neuronal death include the generation of reactive oxygen species during the process of its self-aggregation. When this occurs on the membrane of neurons in vitro, it causes lipid peroxidation and the generation of a toxic aldehyde called 4-hydroxynonenalwhich, in turn, impairs the function of ion-motive ATPases, glucose transporters and glutamate transporters. As a result, amyloid beta promotes depolarization of the synaptic membrane, excessive calcium influx and mitochondrial impairment.[68] Aggregations of the amyloid-beta peptide disrupt membranes in vitro.

Connie’s comments: