Mitochondrial Dysfunction and Mitophagy Closely Cooperate in Neurological Deficits Associated with Alzheimer’s Disease and Type 2 Diabetes

Paul, Sangita; Saha, Debarpita; Binukumar, B.

doi:10.1007/s12035-021-02365-2

Cited by 20 publications

(9 citation statements)

References 198 publications

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“…These individuals exhibit brain hypometabolism, rapidly accumulate new Aβ, and are at greatly increased risk of developing symptomatic AD ( Sperling et al, 2011 ; Lowe et al, 2014 ). Furthermore, it is thought that over half of the older adult population may have peripheral metabolic impairments (i.e., metabolic syndrome, insulin resistance, type 2 diabetes) ( Denys et al, 2009 ), conditions increasingly linked to mitochondrial dysfunction and higher risk of AD-related neurodegeneration and cognitive decline ( Morris et al, 2014b ; Paul et al, 2021 ). For these reasons, both groups are ideal populations in which to test potential AD therapies that specifically target bioenergetic metabolism.…”

Section: Introductionmentioning

confidence: 99%

Potential for Ketotherapies as Amyloid-Regulating Treatment in Individuals at Risk for Alzheimer’s Disease

et al. 2022

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Alzheimer’s disease (AD) is a progressive neurodegenerative condition characterized by clinical decline in memory and other cognitive functions. A classic AD neuropathological hallmark includes the accumulation of amyloid-β (Aβ) plaques, which may precede onset of clinical symptoms by over a decade. Efforts to prevent or treat AD frequently emphasize decreasing Aβ through various mechanisms, but such approaches have yet to establish compelling interventions. It is still not understood exactly why Aβ accumulates in AD, but it is hypothesized that Aβ and other downstream pathological events are a result of impaired bioenergetics, which can also manifest prior to cognitive decline. Evidence suggests that individuals with AD and at high risk for AD have functional brain ketone metabolism and ketotherapies (KTs), dietary approaches that produce ketone bodies for energy metabolism, may affect AD pathology by targeting impaired brain bioenergetics. Cognitively normal individuals with elevated brain Aβ, deemed “preclinical AD,” and older adults with peripheral metabolic impairments are ideal candidates to test whether KTs modulate AD biology as they have impaired mitochondrial function, perturbed brain glucose metabolism, and elevated risk for rapid Aβ accumulation and symptomatic AD. Here, we discuss the link between brain bioenergetics and Aβ, as well as the potential for KTs to influence AD risk and progression.

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Section: Introductionmentioning

confidence: 99%

Potential for Ketotherapies as Amyloid-Regulating Treatment in Individuals at Risk for Alzheimer’s Disease

et al. 2022

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“…The tricarboxylic acid (TCA) cycle of glycolysis occurs in the mitochondria and is accompanied by energy generation. Hyperglycemia state can lead to mitochondrial calcium ion imbalance, dysregulation of the electron transport chain, and disturbed membrane potential, leading to a state of oxidative stress in mitochondria (Paul et al, 2021b). It is also revealed that blood glucose fluctuations, either hyperglycemic or hypoglycemic, can lead to oxidative stress and mitochondrial dysfunction, which is an overall concept that encompasses abnormalities in morphology and physiological function (Carvalho and Cardoso, 2021).…”

Section: Mitochondria Dysfunctionmentioning

confidence: 99%

Hypoglycemic medicines in the treatment of Alzheimer’s disease: Pathophysiological links between AD and glucose metabolism

Wang

Liu

et al. 2023

Front. Pharmacol.

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Alzheimer’s Disease (AD) is a global chronic disease in adults with beta-amyloid (Aβ) deposits and hyperphosphorylated tau protein as the pathologic characteristics. Although the exact etiology of AD is still not fully elucidated, aberrant metabolism including insulin signaling and mitochondria dysfunction plays an important role in the development of AD. Binding to insulin receptor substrates, insulin can transport through the blood-brain barrier (BBB), thus mediating insulin signaling pathways to regulate physiological functions. Impaired insulin signaling pathways, including PI3K/Akt/GSK3β and MAPK pathways, could cause damage to the brain in the pathogenesis of AD. Mitochondrial dysfunction and overexpression of TXNIP could also be causative links between AD and DM. Some antidiabetic medicines may have benefits in the treatment of AD. Metformin can be beneficial for cognition improvement in AD patients, although results from clinical trials were inconsistent. Exendin-4 may affect AD in animal models but there is a lack of clinical trials. Liraglutide and dulaglutide could also benefit AD patients in adequate clinical studies but not semaglutide. Dipeptidyl peptidase IV inhibitors (DPP4is) such as saxagliptin, vildagliptin, linagliptin, and sitagliptin could boost cognitive function in animal models. And SGLT2 inhibitors such as empagliflozin and dapagliflozin were also considerably protective against new-onset dementia in T2DM patients. Insulin therapy is a promising therapy but some studies indicated that it may increase the risk of AD. Herbal medicines are helpful for cognitive function and neuroprotection in the brain. For example, polyphenols, alkaloids, glycosides, and flavonoids have protective benefits in cognition function and glucose metabolism. Focusing on glucose metabolism, we summarized the pharmacological mechanism of hypoglycemic drugs and herbal medicines. New treatment approaches including antidiabetic synthesized drugs and herbal medicines would be provided to patients with AD. More clinical trials are needed to produce definite evidence for the effectiveness of hypoglycemic medications.

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“…As explained above, all these chronic conditions can induce neuronal stress in the CNS. Interestingly, type 2 diabetes and AD share several pathologies, including insulin resistance (see below), dysregulation of glucose and insulin signaling [ 159 ], Aβ deposition [ 160 ] and cognitive impairment [ 161 ], and mitochondrial dysfunction [ 162 ], which is the basis for some researchers to call AD “type 3 diabetes” [ 163 ]. Furthermore, several epidemiological studies have demonstrated a higher risk of AD in patients suffering diabetes [ 160 , 164 ].…”

Section: Human Chronic Pathologies Leading To Neuronal Stressmentioning

confidence: 99%

The Cause of Alzheimer’s Disease: The Theory of Multipathology Convergence to Chronic Neuronal Stress

Decourt¹,

D’Souza²,

Shi³

et al. 2022

Aging and disease

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The field of Alzheimer’s disease (AD) research critically lacks an all-inclusive etiology theory that would integrate existing hypotheses and explain the heterogeneity of disease trajectory and pathologies observed in each individual patient. Here, we propose a novel comprehensive theory that we named: the multipathology convergence to chronic neuronal stress. Our new theory reconsiders long-standing dogmas advanced by previous incomplete theories. Firstly, while it is undeniable that amyloid beta (Aβ) is involved in AD, in the seminal stage of the disease Aβ is unlikely pathogenic. Instead, we hypothesize that the root cause of AD is neuronal stress in the central nervous system (CNS), and Aβ is expressed as part of the physiological response to protect CNS neurons from stress. If there is no return to homeostasis, then Aβ becomes overexpressed, and this includes the generation of longer forms that are more toxic and prone to oligomerization. Secondly, AD etiology is plausibly not strictly compartmentalized within the CNS but may also result from the dysfunction of other physiological systems in the entire body. This view implies that AD may not have a single cause, but rather needs to be considered as a spectrum of multiple chronic pathological modalities converging to the persistent stressing of CNS neurons. These chronic pathological modalities, which include cardiovascular disease, metabolic disorders, and CNS structural changes, often start individually, and over time combine with other chronic modalities to incrementally escalate the amount of stress applied to CNS neurons. We present the case for considering Aβ as a marker of neuronal stress in response to hypoxic, toxic, and starvation events, rather than solely a marker of AD. We also detail numerous human chronic conditions that can lead to neuronal stress in the CNS, making the link with co-morbidities encountered in daily clinical AD practice. Finally, we explain how our theory could be leveraged to improve clinical care for AD and related dementia in personalized medicine paradigms in the near future.

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Mitochondrial Dysfunction and Mitophagy Closely Cooperate in Neurological Deficits Associated with Alzheimer’s Disease and Type 2 Diabetes

Cited by 20 publications

References 198 publications

Potential for Ketotherapies as Amyloid-Regulating Treatment in Individuals at Risk for Alzheimer’s Disease

Potential for Ketotherapies as Amyloid-Regulating Treatment in Individuals at Risk for Alzheimer’s Disease

Hypoglycemic medicines in the treatment of Alzheimer’s disease: Pathophysiological links between AD and glucose metabolism

The Cause of Alzheimer’s Disease: The Theory of Multipathology Convergence to Chronic Neuronal Stress

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