The use of neuropathology in Alzheimer’s disease

doi:10.15406/icpjl.2016.02.00057

eISSN: 2471-0016

International Clinical Pathology Journal

Mini Review Volume 2 Issue 6

The use of neuropathology in Alzheimer’s disease

Siddhartha M ondragon Rodriguez^1,2,3

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¹CONACyT National Council for Science and Technology, M
¹CONACYT National Council for Science and Technology, M
²UNAM Developmental Neurobiology and Neurophysiology, National Autonomous University of M
²UNAM Developmental Neurobiology and Neurophysiology, National Autonomous University of M
³Department of Psychiatry, McGill University, Canada
³Department of Psychiatry, McGill University, Canada

Correspondence: Siddhartha Mondragon-Rodriguez, Ph.D., Developmental Neurobiology and Neurophysiology, Institute of Neurobiology, National Autonomous University of Mexico. Boulevard Juriquilla 3001, Juriquilla, 76230 Santiago de Querétaro, Qro, Mexico, Tel (442)-238-1057

Received: January 01, 1971 | Published: August 22, 2016

Citation: Mondragon-Rodriguez S. The use of neuropathology in Alzheimer’s disease. Int Clin Pathol J. 2016;2(6):128–129. DOI: 10.15406/icpjl.2016.02.00057

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Mini review

Alzheimer’s disease (AD) has been historically defined by protein accumulation around critical areas of the brain, i.e. hippocampus.¹ The hippocampus is a relatively small brain structure located within the limbic system.¹Functionally, this particular structure has been correlated with cognitive functions such as learning, memory and spatial navigation.² In line with this reasoning and thinking in terms of brain disease development, is not difficult to imagine hippocampal damage associated with pathologies like AD.^1,3 Here two proteins are the major players circumscribing the pathological development of AD: amyloid beta (Aβ) and tau proteins.^3,4 Although the exact or the mayor mechanism of protein deposition remains under extensive study, the reality is that we do not know how or why these proteins elicit the accumulation process. However, we need to acknowledge that several pieces of evidence are clues of the putative mechanism. Evidence in support of the case for Aβ: we know that gene mutation in the amyloid precursor protein generates a 42amino acid peptide that is susceptible to extracellular aggregation during the course of AD development.⁵ This peptide is the main component of the extracellular Aβ plaque (Figure 1, black arrows). In addition, we know that the Aβ plaque presents preferentially a spherical shape that can be clearly observed around the limbic area (Figure 1, black arrows). Unfortunately and despite this remarkable finding, the gene mutation corresponding as causal mechanism only accounts for the hereditary form of AD.⁶ In this regard, the second and most predominant form of AD is sporadic, and for this particular type, the mechanism remains unknown.⁶ We need to mention that the sporadic form of AD accounts for more than 95 percent of the cases.⁶

Evidence in support of the case for tau protein; of note, remains far more complex and under extensive study.^3,6 What we know is that tau protein is susceptible of suffering several posttranslational modifications such as conformational shifts, cleavages and several phosphorylation events.^1,3 The current hypothesis holds that a combination of those events prompts the tau protein to an aggregation state. Thus giving rise to the neurofibrillary tangle (NFT), which normally adopts a flame like shape (Figure 1, red arrows). Important to note that opposite to the Aβ plaque which is an extracellular protein deposit, the NFTs are intracellular protein aggregates.^1,3 In agreement with previous published data, we have observed that the NFTs are mainly comprised of phosphorylase tau protein.³

Clearly, both aggregates are related to the AD pathological development; however the main question is how do the aggregates can affect the hippocampal function? Although the answer is far from simple, one thing is clear; both structures can affect the homeostasis of neuronal function. In one hand the Aβ plaque locates preferentially in the proximity of synaptic terminals with the capacity of modifying the neuronal responses.^4,7 On the other hand the extensive tau accumulation within the neuron takes all the intracellular space that ultimately leads to neuronal death (Figure 1). Despite this data, we cannot definitively name either of these structures as the cause of the disease. In fact, the chronology of events remains under extensive study. In this vein, we found that phosphorylation of tau protein is an early event that can function as an early stage developmental biomarker in tau pathologies such as Pick disease, Down syndrome and AD.^8,9 More recently, by using transgenic mouse models, we have found that abnormally phosphorylase tau protein is actually present before any signs of Aβ peptides (in preparation). This data is extremely important if we take into consideration that Aβ has traditionally been suggested as the effector of tau alterations.¹⁰ This data opens a new perspective in terms of chronology and pathology effectors. In addition, our data could offer an explanation of the current failure for therapeutic strategies directed against Aβ proteins.¹⁰ Most likely, we are working with agents directed against the wrong therapeutic target, although this remains to be proven.¹⁰

Overall, it is clear that both structures, the Aβ plaques and the NFTs, are intimately related to AD and several associated brain pathologies such as hereditary cerebral hemorrhage with amyloidosis Dutch type, vascular dementia, Pick disease, Down syndrome and Parkinson’s disease.^3,8,9,11 However, only the neuropathological studies will provide a differential diagnosis between brain diseases. As a consequence, they remain as the most accurate predictors of neurodegeneration stage.

Financial & competing interest’s disclosure

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript.

Acknowledgements

The authors thank Francis Manno III and Keiry Mariana García Méndez for critical comments and technical support. Siddhartha Mondragón-Rodríguez was awarded a Cátedra support from CONACYT, Mexico.