Alzheimer’s altered protein suggesting a common pathway for this

Alzheimer’s
disease (AD) and Parkinson’s disease (PD) are both central nervous system and age
related neurodegenerative diseases characterized by slowly progressive loss on
neurons (Gandhi& Abramov 2012). AD is a progressive neurologic disease that
results in the irreversible loss of neurons, in the cortex and hippocampus
characterized by progressive cognitive decline. Two major pathological
hallmarks of AD are accumulation beta Amyloid- A? peptide and
hyper-phosphorylation of tau (Xie, Gao, Xu & Megn, 2014). On the other
hand,
Pathologically, PD is highlighted by degeneration of dopamine neurons in the
substantia nigra pars compacta and the aggregation of a-synuclein protein in
Lewy body inclusion in the brain. Symptoms that characterize PD include
tremors, rigidity and slower movement (Xie, Gao, Xu & Megn, 2014). Although
AD and PD have distinct mechanisms of etiology, different brain regions and
distinct clinical features, A multitude of research points to the possibility
of a pathologic overlap between the two disorders, especially in the
development of neurodegeneration. Therefore, the aim of this essay is to
discuss the evidence that while PD and AD are distinct neurological disorders
there are some similarities as well as some differences in the underlying
biological mechanisms of these disorders.

 

A common
pathological mechanism of AD and PD is the accumulation of the altered protein suggesting
a common pathway for this two neurodegenerative disorders. However, the protein
involved in each is different, AD is characterized by insoluble protein deposit
of A? plaques and tau- containing neurofibrillary lesions; and a-
synuclein containing Lewy bodies in PD. A multitude of research, suggest that
accumulation of disposal A? are the primary cause of AD, this is called the
amyloid hypothesis. According to the amyloid hypothesis stages of A?
aggregation disrupt cell communication and activate immune cells, this cells
trigger inflammation therefore the brain cells are destroyed (Hardy et al.,
2014). Different lines of evidence support the amyloid
hypothesis. Genetic studies provide the strongest evidence and emphasize the
role of A? as a key initiator of the disease. It was discovered that familial
AD was caused by mutation of APP gene or mutation in the presenilin 1 and 2
which are involved in cutting A? from APP. Also individuals with down syndrome
who have three copies of the chromosome carrying the APP almost always develop
amyloid plaques by the age of forty. Brouillette et al, (2012) developed a new
in vivo technique to investigate the effects of small, soluble A?1– 42  oligomers. 
One week after Bilateral cannulae were implanted in the DG, freely
moving and awake mice received hippocampal injections of soluble A?42 oligomers and vehicle every day
for six days, mice than were killed 24 hours after they received their last
injection.  It was observed that A?1– 42  oligomers had accumulated in the DG and
neuronal death was observed in the surrounding areas of oligomer deposition. To
determine the role of toxic A?1– 42  oligomers which had accumulated for three and
six days the authors further performed a hippocampal protein extraction.

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Similar amounts of the different A?1– 42  oligomers were obtained 3 and 6 days after
injections suggesting that A? oligomers accumulated at the level of cell
bodies. Importantly cell death was not only observed in the dorsal hippocampus
but also in the ventral part of the hippocampus. While pathogenesis of AD is
explained by the amyloid hypothesis, Hasegawa et al (2016) argued that although
the association between amyloid plaques and AD is evident, treatment with anti
A? antibodies does not always ease symptoms in experimental animal trials.

Also, in a clinical trial, an experimental vaccine was observed to clear the
amyloid plaques, however this did not have any significant effect on dementia
(Homel., et al 2008).

 

Similarly, PD is also a disease of protein misfolding,
highlighted by the aggregation of a-synuclein protein in Lewy body inclusion in
the brain. Lewy bodies is a key area of the brain responsible for movement. For
reasons that are not completely clear this protein are altered and aggregate
into Lewy bodies, tangles and plaques. A great deal of research suggests that this
process is very closely linked to neurodegeneration. Although, studies of human
genetics have demonstrated that mutation of (A53T,
A30P, E46K) and multiplication of the ?-syn gene are very closely related to
familial PD and overexpression of human A53T mutant a-syn can lead to severe
movement disorders in mice, the molecular mechanism of a-syn toxicity are not
very clear. Li et al (2013) found that mitochondrial dysfunction was very closely
linked to PD and A53T ?-syn selectively inhibited mitochondrial mobility.

However, the impact of impaired mitochondrial induced by a-syn on
neurodegeneration is still incompletely understood. Therefore, Bido, Soria,
fan, bezard and Tieu, (2017) investigate whether protecting mitochondrial
functioning will be able to decrease a-syn induced neurotoxicity in a vivo
approach.

Despite The recent advancements in AD and
PD genetics the etiology of these diseases remains unclear. Environmental
factors have gained importance and oxidative stress have been found to play a
central role in the pathogenesis of these neurodegenerative diseases. Oxidative
stress occurs when three is an imbalance between the production of reactive
oxygen species(ROS) and a biological system’s ability to detoxify the reactive
intermediates or to repair the resulting damage. (Cenini , 2016).  Although, different studies have investigated
the changes of markers of oxidative damage on late stage AD patients, early stages
of AD progressions are extremely important to determine the role that oxidative
damage plays on the pathogenesis of the disease. Therefore, A study of brains
which investigated AD in different stages demonstrated increased levels of
4-hydroxyhezenal (HHE) (a marker of lipid peroxidation involved in the early
stages of the disease (Bradley, Xiong-Fister, Markesbery , 2012). In
this study the authors quantified the levels of extractable and protein-bound HHE in the hippocampus/parahippocampus gyrus, (HPG),
superior and middle temporal gyri(SMTG), and the cerebellum of mild cognitive impairment,
preclinical AD, late stage AD and a normal control group. using gas chromatography
mass spectrometry, the authors found a significance increase in the levels of
extractable HHE in HPG of PCAD and LAD participants in comparison to normal
control group. However, no difference was found in HPG of MCI participants in
comparison to the control group. Similarly, significant levels of elevation
were observed in protein bound HEE in HPG of MCI, PCAD, and LAD participants in
comparison to the control group. It was further examined whether treatment with
HHE will aid the survival of primary cortical neurons