How is your competent? doctor putting all three of these pieces of research together to prevent your likely dementia? DOING NOTHING, LIKE USUAL?
With your elevated chances of dementia post stroke, your competent? doctor is responsible for preventing that! Have they taken on that responsibility? Or are they DOING NOTHING?
With your chances of getting dementia post stroke you need solutions. YOUR DOCTOR IS RESPONSIBLE FOR PREVENTING THIS!
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:
Bridging brain insulin resistance to Alzheimer’s pathogenesis
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Keywords
biliverdin reductase-A (BVR-A)
insulin
mitochondria
type 2 diabetes mellitus
cognition
neurodegeneration
Links between metabolic disorders and neurodegeneration
Growing
evidence suggests that T2DM and AD share common pathological
mechanisms, notably insulin resistance. Epidemiological studies have
shown that individuals with T2DM are at higher risk of developing AD [1]. Targeting 14 modifiable risk factors, including T2DM and obesity, could prevent nearly half of all dementia cases [2], offering hope for disease-modifying treatments.
In
both conditions of T2DM and obesity, insulin resistance is a common
pathophysiological feature and is usually associated with metabolic
tissues; it manifests uniquely in the brain as BIR [3].
Characterized by reduced responsiveness of brain cells to insulin, BIR
significantly affects cognitive functions, mood regulation, and overall
brain health [4].
BIR
has been linked to key AD features, such as amyloid-beta (Aβ)
accumulation, tau hyperphosphorylation, and neuroinflammation, leading
to neuronal death and cognitive decline [3].
Furthermore, BIR disrupts brain glucose metabolism and further
contributes to energy deficits and impaired brain function. Thus,
understanding how these AD hallmarks interact with BIR to confer the
accelerated AD risk could offer new avenues for therapeutic
intervention.
BVR-A: a pleiotropic protein at the crossroads of metabolic signaling and neurodegeneration
A recent study by Lanzillotta et al. provides new insights into this connection between neurodegenerative diseases and metabolic dysfunctions [5]. Lanzillotta et al.
showed that BVR-A regulates insulin signaling and mitochondrial
function through phosphorylation of GSK3β. In brains of T2DM rats, BVR-A
levels were reduced, impairing insulin signaling, mitochondrial
activity, and cognitive performance, suggesting key roles of BVR-A in
the diabetic brain.
Primarily recognized for its role in heme degradation [6], BVR-A is a critical signaling molecule converting biliverdin into bilirubin (Figure 1A).
Beyond its enzymatic function, evidence demonstrates that BVR-A also
regulates cell survival, neuroprotection, and inflammation. Using animal
models, cell lines, and human subjects with T2DM and AD (Figure 1B), Lanzillotta et al.
present compelling evidence that reduced brain BVR-A disrupts the
Akt–GSK3β signaling axis, essential for glycogen synthesis, cell
survival, and neuroplasticity. As a scaffold protein [7],
BVR-A facilitates Akt binding to GSK3β, leading to GSK3β
phosphorylation at Ser9, a modification essential for its inactivation.
Inactivated GSK3β is neuroprotective, promoting cell survival and
enhancing mitochondrial function. Loss of BVR-A causes mitochondrial
dysfunction and diminished ATP production (Figure 1C),
contributing to BIR. Given the involvement of GSK3β in tau
phosphorylation and Aβ production, these findings are particularly
relevant to AD pathology.
Figure 1. Role of biliverdin reductase-A (BVR-A) in the pathogenesis of brain insulin resistance (BIR) and Alzheimer’s disease (AD).
(A) The primary role of BVR-A in heme metabolism. (B) Experimental approach used by Lanzillotta et al. [5],
which involved animal models of type 2 diabetes mellitus (T2DM), cell
lines, and patients with T2DM and AD. (C) Novel roles of BVR-A in health
and in the pathogenesis of BIR, revealed by Lanzillotta et al.,
in the regulation of insulin receptor substrate 1 (IRS1) activation, as
a scaffold protein for the binding of Akt to glycogen synthase kinase
3β (GSK3β), and as a shuttle for moving GSK3β into mitochondria. See
main text for details. Abbreviations: CO, carbon monoxide; KO, knockout;
MCI, mild cognitive impairment; PBMC, peripheral blood mononuclear
cells; UPRmt, mitochondrial unfolded protein response.
A
major contribution of this study is the elucidation of how impaired
BVR-A function leads to mitochondrial dysfunction in the hippocampus, a
region critical for learning, memory, and early Aβ deposition [8]. The hippocampus is susceptible to metabolic perturbation and oxidative stress [9], making it a primary target for impaired insulin signaling. Lanzillotta et al.
observed that reduced BVR-A levels in T2DM rats were associated with
decreased mitochondrial respiration, leading to insufficient energy for
neuronal function, synaptic dysfunction, and cognitive decline. These
findings underscore the essential role of BVR-A in sustaining cellular
energy homeostasis.
Therapeutic potential of mitochondrial unfolded protein response
The
study also revealed that activation of the mitochondrial unfolded
protein response (UPRmt) acts as a compensatory and protective mechanism
in response to mitochondrial stress in the diabetic brain. Upregulation
of UPRmt proteins reflects an adaptive response to reduced BVR-A levels
and impaired GSK3β inhibition, consistent with established mechanisms
of mitochondrial stress response [10].
Additionally, a parallel antioxidant response suggests a coordinated
effort to protect neurons from oxidative stress. While this dual
activation may represent an early protective phase during
T2DM-associated neuropathy development, the long-term efficacy of UPRmt
activation in preventing neurodegeneration remains uncertain.
Notably,
higher UPRmt protein levels were observed in patients with T2DM
receiving antidiabetic medication. Postmortem examination of individuals
with AD and mild cognitive impairment (MCI) revealed that BVR-A levels
were reduced in MCI brains, while Atf5, a key mediator of UPRmt, was
elevated, suggesting an early compensatory response during AD
progression. Although further validation is needed in larger studies,
these findings offer potential therapeutic strategies for addressing BIR
and mitochondrial dysfunction before AD onset.
By
highlighting the roles of BVR-A in these processes, the present study
opens new avenues for exploring how BVR-A modulation could ameliorate
metabolic and cognitive deficits associated with T2DM and AD.
Lanzillotta et al. provided exciting evidence, albeit on
rodents, demonstrating that intranasal insulin administration
effectively increased BVR-A activity in the hippocampus, restoring
insulin signaling and mitochondrial function. Additionally, targeting
the UPRmt and antioxidant pathways may offer further therapeutic
potential to enhance the natural defenses of the brain against metabolic
stress and mitochondrial dysfunction. These findings suggest BVR-A
modulation as a dual strategy, improving insulin sensitivity and
mitochondrial health in the broader contexts of neurodegeneration.
Further investigations should explore the broader implications of BVR-A
in other neurodegenerative diseases characterized by insulin resistance
and mitochondrial dysfunction, including Parkinson's disease. BVR-A also
holds promise as a biomarker for early detection of BIR, enabling
earlier diagnosis and intervention in individuals at higher risk of
neurodegenerative conditions.
Concluding remarks
While
this study provides valuable insights, several questions remain,
particularly regarding how its activity changes during the progression
of insulin resistance to neurodegeneration and whether there is a cell
type-specific role of BVR-A in the brain. Exploring these mechanisms
could clarify the broader role of BVR-A in metabolism and insulin
sensitivity and, thus, identify new therapeutic targets. Furthermore,
understanding how BVR-A modulates stress responses, such as the UPRmt,
and its interactions with pathways, such as autophagy or the endoplasmic
reticulum stress response, could provide a more comprehensive view of
cellular responses to metabolic stress and inform future therapeutic
strategies.
In conclusion, the work by Lanzillotta et al.
advances our understanding of the molecular underpinnings of BIR and
its connection to mitochondrial dysfunction, positioning BVR-A as a
critical regulator of insulin signaling and a promising therapeutic
target for neurodegenerative diseases. By improving both insulin
sensitivity and mitochondrial function, BVR-A modulation holds potential
for addressing the metabolic roots of brain diseases. As research
continues, exploring the broader implications of BVR-A dysfunction
across tissues could lead to new therapeutic strategies benefiting both
metabolic and cognitive health.
Acknowledgments
Figure 1 was created with BioRender (biorender.com
). This work was supported by grants from NIH T32 (DK007260, to W.C.), the Steno North American Fellowship awarded by the Novo Nordisk Foundation (NNF23OC0087108, to W.C.), and the LundbeckFonden Ascending Investigator Program awarded by the Lundbeck Foundation (LFR344-2020-989, to C.L.Q.).
Declaration of interests
C.L.Q.
has received consultancy fees from Pfizer. She has also received
honoraria, travel, or speakers’ fees from Biogen, and research funds
from Pfizer and Novo Nordisk; she is the director of BrainLogia.
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