Alzheimer's disease biomarkers: Correspondence between human studies and animal models

BackgroundPhysiological brain function depends on tight glucose regulation, including transport and phosphorylation, the first step in its metabolism. Impaired glucose regulation is increasingly implicated in the pathophysiology of Alzheimer's disease (AD). Glucose hypometabolism in AD may be at least partly due to impaired glucose transport at the blood-brain barrier (BBB). Glucose transporters (GLUTs) are an integral component of the BBB. There is evidence of a significant reduction in vascular and non-vascular forms of GLUT1 and GLUT3 in AD brains compared to age-matched controls. Glucose transport, as well as phosphorylation, appears to be a rate limiting step for glucose metabolism in the brain. We have reviewed the literature on glucose transport abnormalities in AD and the effect such abnormalities have on the brain.MethodPublished literature between 1st January 1946 and 1st November 2019 was identified using EMBASE and MEDLINE databases and titles and abstracts were scanned. Human studies (autopsy and imaging) and data from animal models were included while reviews, letters and cellular or molecular studies were excluded from the search.ResultAutopsy studies in AD patients show significant reductions in GLUT3 in areas of the brain closely associated with AD pathology. Patients with AD and diabetes showed greater reductions of GLUT1 and GLUT3. A longitudinal study showed significant reductions in GLUT3 levels which correlated with greater amyloid-β (Aβ) and neurofibrillary tangle pathological burden in participants with AD pathology at post-mortem but without evidence of cognitive dysfunction in their lifetime. Some studies showed increased GLUT1, with others showing reduced GLUT1, levels in AD brain. A newly recognised GLUT12 appears to be increased in AD. Animal studies showed similar results with GLUT1 and GLUT3 knockout animal models exhibiting AD pathology, while overexpression of GLUT1 or treatment with metformin decreased Aβ toxicity in a Drosophila model of AD. GLUT2 levels were increased in both human AD brain and in an animal model of AD. Imaging studies using fluorodeoxyglucose [18F]FDG with positron emission tomography (FDG-PET) in AD subjects show reductions in glucose transport and glucose metabolism in areas most affected in AD. A small randomised control trial showed anti-diabetic medications improved the glucose transport in AD subjects.ConclusionGLUTs play a significant role in AD pathology with evidence suggesting that GLUT3 reductions may precede the onset of clinical symptoms, while GLUT2 and GLUT12 may have a compensatory role. Repurposing anti-diabetic drugs shows promising results in both animal and human studies of AD.

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Faculty Opinions recommendation of Exercise and Alzheimer's disease biomarkers in cognitively normal older adults.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.5414956.5527067 ◽

2010 ◽

Author(s):

Elio Scarpini ◽

Daniela Galimberti

Keyword(s):

Alzheimer’S Disease ◽

Older Adults ◽

Alzheimer's Disease ◽

Cognitively Normal ◽

Disease Biomarkers

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Faculty Opinions recommendation of A culture-brain link: Negative age stereotypes predict Alzheimer's disease biomarkers.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.725999985.793512257 ◽

2016 ◽

Author(s):

Gerd Kempermann

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Age Stereotypes ◽

Disease Biomarkers

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Consideration of a Pharmacological Combinatorial Approach to Inhibit Chronic Inflammation in Alzheimer’s Disease

Current Alzheimer Research ◽

10.2174/1567205016666191106095038 ◽

2019 ◽

Vol 16 (11) ◽

pp. 1007-1017 ◽

Cited By ~ 1

Author(s):

James G. McLarnon

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Animal Models ◽

Chronic Inflammation ◽

Preventive Strategy ◽

Subsequent Work ◽

Activated Microglia ◽

Starting Point ◽

Anti Inflammatory ◽

Cocktail Approach

A combinatorial cocktail approach is suggested as a rationale intervention to attenuate chronic inflammation and confer neuroprotection in Alzheimer’s disease (AD). The requirement for an assemblage of pharmacological compounds follows from the host of pro-inflammatory pathways and mechanisms present in activated microglia in the disease process. This article suggests a starting point using four compounds which present some differential in anti-inflammatory targets and actions but a commonality in showing a finite permeability through Blood-brain Barrier (BBB). A basis for firstchoice compounds demonstrated neuroprotection in animal models (thalidomide and minocycline), clinical trial data showing some slowing in the progression of pathology in AD brain (ibuprofen) and indirect evidence for putative efficacy in blocking oxidative damage and chemotactic response mediated by activated microglia (dapsone). It is emphasized that a number of candidate compounds, other than ones suggested here, could be considered as components of the cocktail approach and would be expected to be examined in subsequent work. In this case, systematic testing in AD animal models is required to rigorously examine the efficacy of first-choice compounds and replace ones showing weaker effects. This protocol represents a practical approach to optimize the reduction of microglial-mediated chronic inflammation in AD pathology. Subsequent work would incorporate the anti-inflammatory cocktail delivery as an adjunctive treatment with ones independent of inflammation as an overall preventive strategy to slow the progression of AD.

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Neuropeptides in Alzheimer’s Disease: An Update

Current Alzheimer Research ◽

10.2174/1567205016666190503152555 ◽

2019 ◽

Vol 16 (6) ◽

pp. 544-558 ◽

Cited By ~ 1

Author(s):

Carla Petrella ◽

Maria Grazia Di Certo ◽

Christian Barbato ◽

Francesca Gabanella ◽

Massimo Ralli ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Animal Models ◽

Potential Role ◽

Brain Distribution ◽

Brain Areas ◽

Small Proteins ◽

Current Review ◽

The Central Nervous System ◽

Available Information

Neuropeptides are small proteins broadly expressed throughout the central nervous system, which act as neurotransmitters, neuromodulators and neuroregulators. Growing evidence has demonstrated the involvement of many neuropeptides in both neurophysiological functions and neuropathological conditions, among which is Alzheimer’s disease (AD). The role exerted by neuropeptides in AD is endorsed by the evidence that they are mainly neuroprotective and widely distributed in brain areas responsible for learning and memory processes. Confirming this point, it has been demonstrated that numerous neuropeptide-containing neurons are pathologically altered in brain areas of both AD patients and AD animal models. Furthermore, the levels of various neuropeptides have been found altered in both Cerebrospinal Fluid (CSF) and blood of AD patients, getting insights into their potential role in the pathophysiology of AD and offering the possibility to identify novel additional biomarkers for this pathology. We summarized the available information about brain distribution, neuroprotective and cognitive functions of some neuropeptides involved in AD. The main focus of the current review was directed towards the description of clinical data reporting alterations in neuropeptides content in both AD patients and AD pre-clinical animal models. In particular, we explored the involvement in the AD of Thyrotropin-Releasing Hormone (TRH), Cocaine- and Amphetamine-Regulated Transcript (CART), Cholecystokinin (CCK), bradykinin and chromogranin/secretogranin family, discussing their potential role as a biomarker or therapeutic target, leaving the dissertation of other neuropeptides to previous reviews.

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