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
Keywords
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.1,2,3
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.4 Closure of these “fingers” is mediated by the components of the ESCRT machinery.5 Once closed, autophagosomes are released by dynamin 2 (DNM2)6
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).
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.7
Furthermore, acetylation-mediated regulation of mTORC1 is modulated by
p300/EP300 shuttling between the cytosol and the nucleus.8
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.9 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).10,11,12
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
autophagosomes13 that upregulate autophagy.14
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 WIPI2.15 Importantly, WIPI2 is recruited to the RAB11A-positive recycling endosome membranes by coincident detection of PI3P and RAB11A,16 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.17 Moreover, transcriptional regulators YAP/TAZ induce autophagy by altering the expression of actin cytoskeleton genes.18,19
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.20
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).21
Importantly, studies that have assessed the substrates of autophagy in
the brain have found an enrichment of synaptic and mitochondrial
proteins.22,23
Synaptic activity also regulates autophagy at the synapse.24,25 Exo-endocytosis of the autophagy protein ATG9 is required for presynaptic autophagosome biogenesis.26 Recruitment of ATG9 to RAB11A-positive structures in dendritic spines is essential for postsynaptic autophagy,27
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.3
Autophagy
regulates critical aspects of synaptic function by recycling cargo,
such as presynaptic neurotransmitter vesicles, postsynaptic scaffolding
proteins, and neurotransmitter receptors.25,28
Autophagy impairment leads to increased neuronal activity, potentially
due to reduced degradation of AKAP11 that regulates the cyclic AMP
(cAMP)-PKA pathway29 and the accumulation of the tubular ER in axons, resulting in increased calcium release from the ER.30 Postsynaptic neurotransmitter receptors such as the GABAA receptor31 and AMPA receptor24
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 receptor16 and CCR5 chemokine receptor.32
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.24,25
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 NDP52,21
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.33
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 HSC70.34
Microautophagy, which is less well understood in mammalian cells,
involves the sequestration of proteins destined for lysosomal
degradation by endosomes or lysosomes themselves.35
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).36 Many components of the autophagic pathway also facilitate an unconventional secretion pathway termed secretory autophagy,37 which may be upregulated when the lysosomal degradation of autophagosomes is impaired.38
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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