Changing stroke rehab and research worldwide now.Time is Brain! trillions and trillions of neurons that DIE each day because there are NO effective hyperacute therapies besides tPA(only 12% effective). I have 523 posts on hyperacute therapy, enough for researchers to spend decades proving them out. These are my personal ideas and blog on stroke rehabilitation and stroke research. Do not attempt any of these without checking with your medical provider. Unless you join me in agitating, when you need these therapies they won't be there.

What this blog is for:

My blog is not to help survivors recover, it is to have the 10 million yearly stroke survivors light fires underneath their doctors, stroke hospitals and stroke researchers to get stroke solved. 100% recovery. The stroke medical world is completely failing at that goal, they don't even have it as a goal. Shortly after getting out of the hospital and getting NO information on the process or protocols of stroke rehabilitation and recovery I started searching on the internet and found that no other survivor received useful information. This is an attempt to cover all stroke rehabilitation information that should be readily available to survivors so they can talk with informed knowledge to their medical staff. It lays out what needs to be done to get stroke survivors closer to 100% recovery. It's quite disgusting that this information is not available from every stroke association and doctors group.

Saturday, January 18, 2025

Autophagy, aging, and age-related neurodegeneration

 What will your competent? doctor do with this to ensure you DON'T GET DEMENTIA from your extra risk from your stroke? NOTHING? So, you DON'T have a functioning stroke doctor, do you? Why the hell doesn't the board of directors' have policies to remove incompetent doctors? They also must be fucking incompetent!

Send me hate mail on this: oc1dean@gmail.com. I'll print your complete statement with your name and my response in my blog. Or are you afraid to engage with my stroke-addled mind? No excuses are allowed! You're medically trained; it should be simple to precisely refute all my points with NO EXCUSES!! And what is your definition of competence in stroke? Swearing at me is allowed, I'll return the favor. Don't even attempt to use the tyranny of low expectations as an answer.

1. A documented 33% dementia chance post-stroke from an Australian study?   May 2012.

2. Then this study came out and seems to have a range from 17-66%. December 2013.`    

3. A 20% chance in this research.   July 2013.

4. Dementia Risk Doubled in Patients Following Stroke September 2018 

The latest here:

Autophagy, aging, and age-related neurodegeneration

Cover Image - Neuron, Volume 113, Issue 1

Summary

Autophagy is a conserved mechanism that degrades damaged or superfluous cellular contents and enables nutrient recycling under starvation conditions. Many neurodegeneration-associated proteins are autophagy substrates, and autophagy upregulation ameliorates disease in many animal models of neurodegeneration by enhancing the clearance of toxic proteins, proinflammatory molecules, and dysfunctional organelles. Autophagy inhibition also induces neuronal and glial senescence, a phenomenon that occurs with increasing age in non-diseased brains as well as in response to neurodegeneration-associated stresses. However, aging and many neurodegeneration-associated proteins and mutations impair autophagy. This creates a potentially detrimental feedback loop whereby the accumulation of these disease-associated proteins impairs their autophagic clearance, facilitating their further accumulation and aggregation. Thus, understanding how autophagy interacts with aging, senescence, and neurodegenerative diseases in a temporal, cellular, and genetic context is important for the future clinical application of autophagy-modulating therapies in aging and neurodegeneration.

Keywords

  1. autophagy
  2. neurodegeneration
  3. aging
  4. senescence
  5. Alzheimer’s disease
  6. Parkinson’s disease
  7. motor neuron disease
  8. frontotemporal dementia
  9. Huntington’s disease

Overview of the autophagy process

Macroautophagy (henceforth autophagy) is a fundamental cellular process responsible for the degradation and recycling of cytoplasmic contents. Since its discovery in the 1960s, autophagy has been recognized as a key player in numerous physiological and pathological conditions, including aging and neurodegenerative diseases.
Canonical autophagy is a multistep process that involves a sophisticated interplay of numerous proteins and lipids derived from diverse membrane sources, including the endoplasmic reticulum (ER), ER/mitochondria contact sites (MAM), recycling endosomes, Golgi, and plasma membrane.,, The initiation of autophagy begins with the formation of double-membraned structures known as phagophores, finger-like structures that emerge from the RAB11A-positive recycling endosome compartment and capture substrates. Closure of these “fingers” is mediated by the components of the ESCRT machinery. Once closed, autophagosomes are released by dynamin 2 (DNM2) from their recycling endosome platforms to mature and fuse with the lysosome to produce autolysosomes, allowing for the degradation of luminal contents by lysosomal hydrolases (Figure 1).
Figure 1 Overview of the autophagy pathway
Autophagy is triggered by several responses within the organism, including amino acid starvation, reduced insulin levels, and lowered ATP levels. Nutrient availability and cellular energy status (defined as AMP/ATP levels) are detected by the mammalian target of rapamycin complex 1 (mTORC1) kinase complex and AMP-activated protein kinase (AMPK), respectively. Recently, the amino acid leucine was shown to regulate mTORC1 via its metabolite acetyl-coenzyme A (AcCoA), where elevated AcCoA levels stimulate mTORC1 activity, which inhibits autophagy. Furthermore, acetylation-mediated regulation of mTORC1 is modulated by p300/EP300 shuttling between the cytosol and the nucleus. AMPK promotes autophagy by acting through specific phosphorylation of components of autophagy-related protein complexes. A recent study showed that initial activation of AMPK inhibits autophagy induced by amino acid starvation. However, these effects may be cell type and time dependent.
Both mTORC1 and AMPK signal to the downstream unc-51-like autophagy-activating kinase 1 (ULK1) complex to mobilize the class III phosphatidylinositol 3-kinase (PI3K) complex I to the site of the phagophore formation, where VPS34 kinase, in complex with ATG14, VPS15, and beclin 1, generates phosphatidylinositol-3-phosphate (PI3P). PI3K complex I activity is modulated by its association with valosin-containing protein (VCP, also called p97).,, During glucose starvation, canonical activation of PI3K complex I and synthesis of PI3P lipids can be bypassed through the formation of PIKfyve-dependent phosphatidylinositol-5-phosphate (PI5P)-containing autophagosomes that upregulate autophagy.
The defining molecular event of autophagy is the conjugation of LC3 family members to phosphatidylethanolamine in phagophore membranes (Figure 1). This conjugation is orchestrated by an E3 ligase-like complex of ATG16L1 and the ATG5-ATG12 conjugate and the E1-like ligase ATG7. The recruitment of the ATG16L-5-12 LC3 conjugation machinery is mediated by the interaction between ATG16L1 and the PI3P-binding protein WIPI2. Importantly, WIPI2 is recruited to the RAB11A-positive recycling endosome membranes by coincident detection of PI3P and RAB11A, providing the specificity for autophagosome biogenesis at the recycling endosome.
Autophagy is also regulated at the transcriptional level. The transcription factor EB (TFEB) is a major regulator of starvation-induced autophagy by driving the expression of autophagy and lysosomal genes. Moreover, transcriptional regulators YAP/TAZ induce autophagy by altering the expression of actin cytoskeleton genes.,
Autophagy was initially characterized as a bulk and non-selective degradation pathway to recycle building blocks to compensate for the lack of nutrients during starvation. However, it has subsequently become clear that autophagy promotes intracellular homeostasis by selectively degrading cargo material, such as aggregate-prone proteins that cause Parkinson’s disease (PD) (α-synuclein [α-Syn]), dementias (tau), and Huntington’s disease (HD) (huntingtin [HTT]) in a process called aggrephagy. Thus, along with other proteolytic systems, like the ubiquitin-proteasome pathway, translational control and the chaperone machinery, autophagy helps to maintain protein homeostasis (proteostasis). Recent data have shown that autophagy preferentially degrades the non-fibrillar (amorphous) small aggregates of such proteins rather than the larger fibrillar species. Autophagy also serves as a critical clearance route for organelles, including damaged mitochondria (mitophagy), ER (ERphagy), lysosomes (lysophagy), Golgi (Golgiphagy), synaptic proteins, excess peroxisomes (pexophagy), and invading pathogens (xenophagy). Importantly, studies that have assessed the substrates of autophagy in the brain have found an enrichment of synaptic and mitochondrial proteins.,
Synaptic activity also regulates autophagy at the synapse., Exo-endocytosis of the autophagy protein ATG9 is required for presynaptic autophagosome biogenesis. Recruitment of ATG9 to RAB11A-positive structures in dendritic spines is essential for postsynaptic autophagy, paralleling our earlier observations that ATG9 endocytosis from the plasma membrane and recruitment to the RAB11A compartment is required for autophagosome biogenesis in other cell types.
Autophagy regulates critical aspects of synaptic function by recycling cargo, such as presynaptic neurotransmitter vesicles, postsynaptic scaffolding proteins, and neurotransmitter receptors., Autophagy impairment leads to increased neuronal activity, potentially due to reduced degradation of AKAP11 that regulates the cyclic AMP (cAMP)-PKA pathway and the accumulation of the tubular ER in axons, resulting in increased calcium release from the ER. Postsynaptic neurotransmitter receptors such as the GABAA receptor and AMPA receptor undergo endocytosis followed by autophagy-dependent degradation. We speculate that the autophagic degradation of neurotransmitter receptors occurs via their internalization to the RAB11A-positive recycling endosome, leading to their incorporation into the inner and outer membranes of the autophagosome. This leads to their degradation, as the inner autophagosome membrane is degraded after fusion with lysosomes. We have observed this phenomenon with some plasma membrane-associated transmembrane proteins that arrive at the recycling endosome compartment and are found in the inner (and outer) autophagosome membranes, such as the transferrin receptor and CCR5 chemokine receptor. However, we cannot exclude that there are additional routes for the autophagic degradation of these neurotransmitter receptors, such as the fusion of endocytosed vesicles with autophagosomes. The autophagic degradation of neurotransmitter receptors is essential for normal dendritic spine remodeling and synaptic plasticity processes., Thus, impaired autophagy may exacerbate the progression of neurodegenerative diseases due to defects in synaptic function and neuroplasticity long before neuronal cell death and overt neurodegeneration.
In selective autophagy, cargo receptors act as bifunctional adaptors linking the autophagy substrates, such as mitochondria or protein aggregates, with components of the autophagy machinery, typically LC3 family members. These cargo receptors often recognize K63 ubiquitin chains on the autophagy substrates and typically interact with LC3 family members via LC3-interacting regions, which have a consensus sequence. Examples of common cargo adaptor proteins are p62 (also known as SQSTM1), TAX1BP1, NBR1, optineurin (OPTN), and NDP52, although this list is not exhaustive. The extent to which each adaptor is involved in a particular type of selective autophagy, and the degree of redundancy between different adaptor proteins for the same organelle or substrate, is an area of current research.
In addition to macroautophagy (Figure 1), which is the focus of this review, there are other routes enabling the lysosomal degradation of cytoplasmic proteins. In chaperone-mediated autophagy, substrates are recognized by cytoplasmic HSC70 via a pentapeptide consensus motif, then trafficked into the lysosome via LAMP2A, where they are received by lysosomal HSC70. Microautophagy, which is less well understood in mammalian cells, involves the sequestration of proteins destined for lysosomal degradation by endosomes or lysosomes themselves. Many autophagy proteins, such as beclin 1 and those involved in the LC3 conjugation machinery (e.g., ATG3, ATG5-12, ATG16L1, and ATG7), also function in the conjugation of LC3 to single membranes (CASMs) pathways such as LC3-associated endocytosis (LANDO) and LC3-associated phagocytosis (LAP). Many components of the autophagic pathway also facilitate an unconventional secretion pathway termed secretory autophagy, which may be upregulated when the lysosomal degradation of autophagosomes is impaired.
In this review, we will consider the interplays between autophagy, aging, and late-onset neurodegenerative diseases. We will not aim to provide a comprehensive review of all relevant diseases but instead highlight key links and some less obvious connections in the context of aging and senescence.

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