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Ongoing interest in brain ischemia research
has provided data showing that ischemia may be involved in the etiology of
Alzheimer’s disease. Brain ischemia in animals leads to metabolic and
structural changes within the special brain areas like in Alzheimer’s disease
it is in the hippocampus. Ischemia is the second naturally occurring pathology,
including the Alzheimer's disease, which causes neurons death in the CA1 region
of the hippocampus. Brain ischemia has been found as the most effective
predictor for the development of Alzheimer’s-type dementia. Postischemic
dementia might be the result of direct influence of ischemia, ischemic white
matter changes and Alzheimer’s-type neuropathology, or combinations of these
three. Animals after ischemia with short-term survival up to 6 months showed
strong intracellular staining to the N-terminal of amyloid protein precursor
and to the β-amyloid peptide and as well as to the C-terminal of amyloid
protein precursor. But after 6 months, animals demonstrated strong intracellular
staining only to the β-amyloid peptide as well as to the C-terminal of amyloid
protein precursor. Extracellular metabolite of amyloid protein precursor
deposits especially in hippocampus ranged from numerous widespread small dots
to irregular diffuse plaques. Recent knowledge regarding the activation of
Alzheimer’s-related genes and proteins as well as neuropathology of both brain
ischemia and Alzheimer’s disease indicate that similar processes contribute to
neuronal death and brain parenchyma disintegration and finally dementia. We
present the concept that Alzheimer’s-associated genes and their proteins can
contribute to and/or trigger postischemic brain pathology, including dementia
of Alzheimer’s phenotype. Over time, some brain regions, especially the
hippocampus would become increasingly at risk of chronic ischemia, leading to
progress the neuropathological changes of Alzheimer’s-type. Nevertheless,
altered by ischemia brain predisposes to progressive neuronal damage,
dysfunction and death, induction of Alzheimer's-related genes and proteins and
finally lead to acute or chronic neuropathology, including full-blown dementia
of Alzheimer’s phenotype. Ischemia indicates a vascular system as probable
factor that induces neurodegeneration and full-blown dementia in Alzheimer's
disease.
Key words: Brain ischemia, Alzheimer’s disease, gene,
protein, amyloid protein precursor, presenilin 1 and 2, beta-secretase, tau
protein, autophagy, mitophagy, apoptosis
INTRODUCTION
Alzheimer’s
disease is a progressive and irreversible disease with changes in behavior and
personality and with final diagnosis available post mortem after brain autopsy.
Although there are rare cases with familial form (circa 5%) of Alzheimer’s
disease, the majority of patients have the sporadic form (>95%) of the
disease. This disease is the most important cause of dementia in world aged
society (~75%). The continuing neuronal death in vulnerable brain regions e.g.
in hippocampus and progressive dementia in individuals with Alzheimer’s disease
are related with the presence of extracellular diffuse and senile amyloid
plaques and intraneuronal neurofibrillary tangles in diseased brains neurons.
The recent calculation for population suffering from Alzheimer’s disease is
between 15-20 million patients’ worldwide [Hu et al., 2007]. As the world
population grows and mean life spans go on to lengthen, the incidence of
Alzheimer’s disease is calculated to be between 30-40 million worldwide by 2050
[Hu et al., 2007]. In 2014, the direct cost of Alzheimer’s disease for payers
in the USA alone was estimated to be $214 billion [Winblad et al., 2016]. The
neuropathological changes associated with Alzheimer’s disease begin decades
before the emergence of clinical symptoms. The cause of sporadic Alzheimer’s
disease is unclear. The series of events that lead to neuronal death especially
in hippocampus during disease is not clearly understood. As a result of above,
no etiology, no diagnosis ante mortem and no causal therapy stopping the
progression of this devastating disease is actually present [Pluta et al.,
2013]. The road to clarity of Alzheimer’s disease etiology, early final ante
mortem diagnosis and causal treatment has been one fraught with a wide range of
complications and numerous revisions with a lack of a final solution.
Alzheimer’s
disease is the one of the great health-care challenges of the 21st
century. In December 2013, the G8 stated that dementia including Alzheimer’s
disease type dementia should be made a global priority and their ambition that
a cure or a disease-modifying therapy should be available by 2025 [Scheltens et
al., 2016]. Alzheimer’s disease etiology so far is an unresolved issue, as can
be seen by the Alzheimer’s disease Research Contest announced by the US
Department of Defense at the end of 2017. While the study of Alzheimer’s
disease etiology to date have focused on “amyloid hypothesis” without final
conclusion, other etiology approaches may be necessary. We propose as first an
alternative idea to the “amyloid hypothesis”, the “ischemic theory” of
Alzheimer’s disease [Pluta et al., 1994b, Pluta 2007, Pluta et al., 2009]. At
present, the involvement of brain ischemia in the pathogenesis of sporadic
Alzheimer’s disease has attracted considerable interest.
Alois
Alzheimer in the first case of Alzheimer’s disease reported that in the brain
of Augusta D. he had noted that “a growth appears on the endothelia, in some
places also a proliferation of vessels” and “the larger vascular tissues show
arteriosclerosis changes” [Alzheimer 1907]. It seems that the endothelial
proliferation and revascularization were a direct consequence of the brain
ischemia-reperfusion injury. Endothelial proliferation and blood-brain barrier
vessel angiogenesis and moderate arteriosclerosis in the brain arteries of the
first case provide strong evidence that neurovascular pathologies were also
evident in the original case of Alzheimer’s disease [Alzheimer 1907].
Small
vessel pathology in Alzheimer’s disease
Microvascular
changes have been consistently observed in almost all-human Alzheimer’s disease
brains examined post mortem and in brain biopsy tissue from patients with
Alzheimer’s disease [Kalaria 2002]. Capillary degenerations appear more
prevalent in the hippocampus, a sector that is linked to learning and memory
and is primary target for Alzheimer’s disease and brain ischemia neuropathology
[Pluta 2000, Pluta et al., 2009]. Additionally, microvascular pathology in
Alzheimer’s disease patients did not correlate to the degree of the disease
development and suggest that capillary changes are not a consequence but cause
of neuropathology in Alzheimer’s disease [De Jong et al., 1999]. The different
types of cerebrovascular lesions that have been associated with Alzheimer’s
disease include: 1) presence of cerebral small vessels amyloid angiopathy, 2)
microvascular degeneration (endothelial and pericytes degeneration, basement
lamina thickening, collagen accumulation, tortuosity, fibrohyalinosis,
lipohyalinosis), 3) changes of the blood-brain barrier, 4) white matter lesions
and lacunas, 5) large brain infarcts and microinfarcts and presence of
intracerebral hemorrhages [Kalaria 2002]. Post mortem examination has presented
a very strong correlation between brain capillary amyloid angiopathy and both β-amyloid peptide plaque
accumulation and development of Alzheimer’s disease neuropathology [Attems,
Jellinger 2004]. Experimental ischemic study revealed that almost identical
capillary alterations, as such in Alzheimer’s disease patients, could be formed
in animals with prevalence in CA1 sector of hippocampus [De Jong et al., 1999].
The role of microvascular pathology in Alzheimer’s disease is to this very day
a matter of confusion and controversy.
Dementia
is a general term for symptoms exhibited by people with different kinds of
cognitive impairment. These symptoms may include impaired mental functioning in
areas such as memory, learning, judgment, attention, concentration, language
and thinking. They are often accompanied by personality and behavioral changes.
There seem to be peaks in the incidence of dementia - one in patients in their
early 40’s and 60’s and another in patients in their 70’s and 80’s.
Postischemic dementia of Alzheimer’s disease
phenotype
In Humans
A more
insidious consequence of ischemic brain injury in humans is a progressive
postischemic dementia that is also linked with severe disability [Pluta 2007,
Pluta et al., 2013, Frisch et al., 2017, Sherzai et al., 2018]. Epidemiological
studies have shown that the prevalence of dementia in postischemic brain injury
individuals is 9-fold higher than in controls after 3 months and 4–12 times
higher than in controls 4 years after a lacunar infarct [Pluta 2007, Yang,
Simpkins 2007, Kim, Lee 2018]. Different patterns of cognitive decline, as a
result of postischemic injury, have been evident by longitudinal
epidemiological studies, which have demonstrated a progressive course of
dementia with the incidence rate of 9/100 persons/year. Dementia is the worst
consequence for survivors following brain ischemia and it is responsible for
approximately 20 % of all confirmed dementias [Pluta 2007, Yang, Simpkins 2007,
Pluta et al., 2013]. Globally, dementia, following ischemic stroke, varies from
10 % to 50 % depending on the diagnostic criteria, geographic location and
population demographic [Pluta 2007, Yang, Simpkins 2007, Pluta et al., 2013].
In fact, it is becoming clear that postischemic dementia has many risk factors
in common with sporadic Alzheimer’s disease. Indeed, brain ischemic injuries
may precede the onset of this form of dementia, strongly suggesting that brain
ischemic episodes may trigger neurodegenerative dementias. Postischemic
dementia associated with chronic delayed secondary injury occurs in patients
suffering from focal, lacunar and salient brain ischemia in a progressive
manner [Pluta 2007, Yang, Simpkins 2007, Pluta et al., 2013]. The progressive
postischemic injury has received far less attention in clinical and
experimental dementia studies.
In Animals
In
addition to ischemic neuronal lesions in animals after brain ischemia,
behavioral changes have been shown, too [Bara de la Tremblaye, Plamondon 2011,
Kiryk et al., 2011, Li et al., 2011, Cohan et al., 2015]. Following ischemic
brain injury, locomotor hyperactivity has been observed [Ishibashi et al.,
2006] as in Alzheimer’s disease individuals [Pluta et al., 2013]. Longer
ischemia and longer locomotor hyperactivity, which are positive, correlated
with increased pyramidal neurons loss in hippocampus [Ishibashi et al., 2006].
After ischemic brain injury, impairment in habituation, as revealed by an
increase in exploration time, was observed. Brain ischemia results in reference
and working memory deficits [Kiryk et al., 2011]. Moreover, ischemic brain
injury in animals leads progressively to spatial memory deficits during the
survival period [Kiryk et al., 2011]. In addition, evidence from repetitive
ischemic brain injury has shown persistent locomotor hyperactivity, severe
cognitive deficits and reduced anxiety [Ishibashi et al., 2006]. The behavioral
changes in animals, mentioned above, were associated with significant brain
atrophy and neuronal loss in the CA1 subfield of hippocampus, brain cortex,
caudate nucleus, amygdala, and perirhinal cortex [Ishibashi et al., 2006, Pluta
et al., 2009, Barra de la Tremblaye, Plamondon 2011, Kiryk et al., 2011, Li et
al., 2011, Pluta et al., 2013]. Alertness and sensorimotor capacities are
affected for 1–2 days whereas the deficits in learning and memory seem to be
irreversibly progressing and lasting for good [Kiryk et al., 2011, Pluta et
al., 2013].
Possible factors contributing to cognitive
impairment
Removal
of the above abnormalities is an issue that neurologists and scientists devote
little time to. Ischemic brain injury often leaves its victims functionally
devastated and, as such, is the leading cause of permanent disability requiring
long-term institutional care. The loss of life quality for years and health
care resources are staggering. The situation is even aggravated by the fact
that unlike many cases of other neurological diseases, no safe, causal and
effective therapy is available for the patients with postischemic dementia. The
social burden after brain ischemia is dramatically increasing. Thus,
understanding of the underlying progressing neuropathological processes is
urgently needed.
Taken
together, supporting evidences from both clinical and experimental investigations
showed that the progressive decline of cognitive activities could not be
explained only by the direct contribution of the primary ischemic brain injury,
but rather by a progressive consequence of the additive effects of the
postischemic injury, Alzheimer’s disease associated factors and aging [Pluta et
al., 2013, Popa-Wagner et al., 2018]. The available data suggest that brain
ischemia enhances amyloid protein precursor expression and metabolism, which
may be partly involved in the progression of cognitive impairment in the
postischemic period [Pluta et al., 2009, Pluta et al., 2013, Kocki et al.,
2015, Pluta et al., 2016a, Pluta et al., 2016b, Ułamek-Kozioł et al., 2016,
Ułamek-Kozioł et al., 2017]. At last, the generation of β-amyloid peptide in postischemic
brain parenchyma increases which impairs the memory [Pluta et al., 1991, Pluta
et al., 1994b, Badan et al., 2004, Pluta et al., 2009]. Also overexpression of
tau protein gene and its product was shown after ischemia-reperfusion brain injury
[Tanimukai et al., 1998, Pennypacker et
al., 1999, Pluta 2001, Pluta et al., 2018]. Additionally, pathological
postischemic accumulation of α-synuclein might disrupt synaptic activity, resulting in cognitive
suffering [Pluta et al., 2013]. The functional abnormalities precede the
neuronal degeneration within the areas of selective vulnerability to ischemia.
What is more, areas of brain, which are devoid of ischemic neuronal injury,
display functional abnormalities. The above alterations seem to be mainly due
to synaptic insufficiency in connections of neuronal cells within areas with
ischemically damaged or dead neurons.
Brain ischemia as possible trigger of
sporadic Alzheimer’s disease
Alzheimer’s
disease is characterized by loss of neurons, amyloid plaques, neurofibrillary
tangles, cerebral amyloid angiopathy and dementia development. In Alzheimer’s
disease, there is a positive correlation between areas with heavy β-amyloid peptide deposition and
those which are damaged in the brain [Pluta et al., 2013]. On the other hand,
quantitative measure of β-amyloid
peptide level did not correlate with Alzheimer’s disease duration [Pluta et
al., 2013]. This may be interpreted as follows: it seems that β-amyloid peptide could not
continue accumulating in the brain during the disease development. Although the
extent of neuronal death is directly correlated with the intensification of
dementia [Pluta et al., 2013], the mechanism leading to the neuronal cells loss
still remain unclear. It is a matter of controversy whether the pathological
cascade of β-amyloid peptide
in Alzheimer’s disease is primarily triggered by intraneuronal or extracellular
accumulations of β-amyloid peptide and will
contribute directly or indirectly, if at all, to Alzheimer’s disease development
with massive neuronal loss. Investigation on transgenic animals demonstrates
that the mechanism of neuronal death did not correlate with the presence of tau
protein filament formation within individual neurons which are going to die,
suggesting that neuronal death can occur independently of generation of
neurofibrillary tangles [Andorfer et al., 2005]. Moreover, there is evidence to
support the above results that some neurons in Alzheimer’s disease may die
without forming neurofibrillary tangles [Armstrong 2006, Pluta et al. 2013]. It
can be concluded that there is no relationship between amyloid plaques and
neurofibrillary tangles and developing dementia in Alzheimer’s disease, and
amyloid plaques and neurofibrillary tangles may arise as independent alterations
and can result from a neurodegenerative processes rather than being their
cause. These seem to provide an additional conclusion that neuronal death may
not result directly and/or primarily from amyloid plaques and formation of
neurofibrillary tangles but rather it might be associated with other
pathological factor(s). Another important pathological element in Alzheimer’s
disease is β-amyloid peptide
accumulation in brain small blood vessels. The β-amyloid peptide deposition in
brain small blood vessels causes wall pathology in vascular network and results
in blood–brain barrier changes and focal “no-reflow phenomenon”. The collapse
of such a barrier leads to spread of blood β-amyloid peptide into the
surrounding brain parenchyma [Pluta et al., 1996]. Examination of amyloid
plaques made by using serial sections of Alzheimer’s disease brains by both
electron and light microscopy in order to observe the relationship between
plaques and microvessels can be summarized as follows: (1) The cores of the
typical senile plaques appear in tight contact with the microvessels and the β-amyloid peptide spread into the
surrounding brain parenchyma [Armstrong 2006]. The composition of senile
plaques core includes complement factors and immunoglobulin’s [Armstrong 2006].
The presence of immune proteins within the plaques core suggests that blood
immunological components could be entangled in the structure of β-amyloid peptide deposits. (2)
Different types of plaques have a close link to the capillaries. (3) Both
confocal laser scanning microscopy and scanning electron microscopy
demonstrated a direct link between the β-amyloid peptide and vascular network, especially β-amyloid peptide 1–40.
Additionally, confocal laser scanning microscopy has demonstrated that β-amyloid peptide 1–40 depositions
occur in and around neurovessels. The above mentioned results seem to indicate
that some changes of the blood–brain barrier can induce transport of blood β-amyloid peptide 1–40 into the
brain parenchyma of Alzheimer’s disease patients. (4) The global atrophy of the
brain, especially of the hippocampus and alterations of astrocytic cells
(vascular end-feet) are common hallmarks in Alzheimer’s disease [Armstrong
2006]. From this point of view, dysfunction of the blood–brain barrier is an
important element with regard to the neuropathological damage observed in
Alzheimer’s disease brains.
The
discovery of mutations within amyloid protein precursor gene led to the
suggestion of primary pathological role for metabolite of amyloid protein
precursor in Alzheimer’s disease. This data has supported the formulation of
the “amyloid hypothesis” of Alzheimer’s disease in which the deposition of β-amyloid peptide is the trigger of
neuropathological events in Alzheimer’s disease and of all subsequent
pathologies. Nevertheless, the etiology based on “amyloid hypothesis” of
sporadic Alzheimer’s disease has not yet been cleared up and probably is
baseless. The results presented so far suggest that amyloid protein precursor
and presenilin genes overexpression may not be the direct cause of different
forms of Alzheimer’s disease cases but probably they could influence the
neurochemical components of a resulting pathology, and therefore indirectly
affect the levels of neurotoxicity and extent of secondary neurodegeneration
[Pluta et al., 2013, Kocki et al., 2015, Pluta et al., 2016a, Pluta et al.,
2016b, Ułamek-Kozioł et al., 2017, Pluta et al., 2018]. Conversely, in
transgenic animal brains, with high blood levels of β-amyloid peptide in systemic
circulation, no detectable depositions of β-amyloid peptide appeared [Pluta
et al., 2013]. Basing upon evidence of no difference in the level of blood β-amyloid peptide 1–40 and β-amyloid peptide 1–42 among cases
of sporadic Alzheimer’s disease and control individuals, finding out that more
numerous deposits of β-amyloid
peptide 1–40 and β-amyloid
peptide 1–42 were noted in brains of Alzheimer’s disease patients than in
controls strongly suggests that a certain dysfunction of the blood-brain
barrier could induce an abnormal passage of β-amyloid peptides from systemic
circulation to the brain tissue in Alzheimer’s disease patients [Pluta et al.,
1996]. Additionally, plaque-like degeneration of arteries and capillaries and
considered that the core of senile plaques might consist of material that had
permeated from the circulatory network was observed [Armstrong 2006]. Therefore
passage to and accumulation of serum β-amyloid peptide into the surrounding brain parenchyma and vessel wall
may require interrupted blood–brain barrier. Some risk factors for Alzheimer’s
disease development like brain ischemia are known to disrupt blood–brain
barrier integrity and thereby can allow transportation of peripheral β-amyloid peptide into the
surrounding brain parenchyma [Pluta et al., 1996]. For this reason, a detailed
study on the role of ischemic factor in sporadic Alzheimer’s disease should be
carried out as a priority. It should be mentioned that there is still
controversy whether ischemic-type dementia is a different entity from
Alzheimer’s disease dementia or merely two extreme descriptions of the same
clinical condition. Currently, a considerable and growing body of evidence
suggests that ischemic mechanism(s) in combination with overexpression of
Alzheimer’s disease-connected genes are present in Alzheimer’s disease development
[Pluta et al., 2013, Kocki et al., 2015, Pluta et al., 2016a, Pluta et al.,
2016b, Ułamek-Kozioł et al., 2016, Ułamek-Kozioł et al., 2017, Pluta et al.,
2018]. Lately, brain ischemia has been recognized as a factor lowering the
threshold of neuronal death. Neuropathological post mortem examinations of
Alzheimer’s disease brains have shown that 30% of patients showed evidence of
postischemic injury [Kalaria 2002] and the cases with both Alzheimer’s disease
and brain ischemia demonstrated more severe cognitive impairment than those
without brain ischemia [Snowdon et al., 1997, Li et al., 2011]. Some studies
from transgenic mice demonstrated that neuronal death, a common feature of
Alzheimer’s disease, is not dependent on β-amyloid peptide [Armstrong 2006]. Other studies indicate that β-amyloid peptide is generated as a
response to ischemic neuronal injury which is supported by overexpression genes
of amyloid protein precursor, presenilin1 and 2, and beta-secretase [Kocki et
al., 2015, Pluta et al., 2016a, Pluta et al., 2016b]. In addition, the genes of
autophagy, mitophagy, apoptosis and tau protein were overexpressed following
brain ischemia [Ułamek-Kozioł et al., 2016, Ułamek-Kozioł et al., 2017, Pluta
et al., 2018]. In human cases with brain ischemia, β-amyloid peptide was found in
neuronal bodies and around dystrophic neurites and accumulation of β-amyloid peptide was similar to
depositions seen in Alzheimer’s disease [Qi et al., 2007]. Thus, the increased
staining of different parts of amyloid protein precursor may be a reaction of
the brain to ischemic neuronal injury [Pluta et al., 1994b, Badan et al., 2004,
Pluta et al., 2009, Pluta et al., 2013]. On the other hand, increased synthesis
and metabolism of amyloid protein precursor in patients with brain ischemia may
be an acute response of the genes and proteins to brain ischemic injury leading
to the massive deposition of β-amyloid peptide [Qi et al., 2007]. We propose that amyloid protein
precursor/β-amyloid peptide
is involved in the course of the disease as a secondary pathological factor.
Tau protein pathology can also be a part of the neuronal reaction to brain
ischemia which is supported by overexpression of tau protein gene following
ischemic brain episode [Wen et al., 2007, Pluta et al., 2018]. Experimental
brain ischemia-reperfusion injury has also resulted in overexpression of
amyloid protein precursor gene in the brain cortex and hippocampus, implying
that the production and metabolism of amyloid protein precursor may be a
characteristic response to loss of functional activity by ischemic brain [Kocki
et al., 2015, Pluta et al., 2016a, Pluta et al., 2016b]. To support these
conclusions, different parts of amyloid protein precursor were found in
ischemic neuronal bodies, axonal swellings and dystrophic neurites [Pluta et al.,
1994b, Badan et al., 2004, Pluta et al., 2009, Pluta et al., 2013]. In ischemic
brain, diffuse plaques are connected with field of clusters of neuronal
perikarya and the shape of staining frequently covered dendrite area. In
Alzheimer’s disease, the predominance of neuronal mRNAs in individual plaques
was observed, which suggests that the amyloid plaques develop in the areas
where neurons die [Pluta et al., 2013, Kocki et al., 2015]. The demonstrated
data support the idea that amyloid protein precursor gene and its protein is
upregulated in brain as an effect of neuronal injury and/or loss of functional
innervations, and therefore, that the early development of diffuse plaques in
Alzheimer’s disease may be a result of neuronal degeneration [Kocki et al.,
2015, Pluta et al., 2016a, Pluta et al., 2016b]. Different studies support a
general conclusion that the formation of amyloid plaques and neurofibrillary
tangles is a reactive alteration that appears in response to neuronal ischemic
injury and is not strictly related to dementia [Armstrong 2006]. Nevertheless, β-amyloid peptide is a neurotoxin
when produced and may start processes of secondary neuronal injury. Other data
also suggest that tau protein hyperphosphorylation with overexpression of its
gene is a result of neurodegenerative changes [Wen et al., 2007, Majd et al.,
2016, Fujii et al., 2017, Pluta et al., 2018]. It can be concluded that amyloid
plaques and tau protein changes arise independently. However, once initiated,
pathological processes can mutually cooperate. If β-amyloid peptide and tau protein
alterations are the product of neurodegeneration thus, probably, these two
proteins are hallmarks of late stages in sporadic Alzheimer’s disease
development. We would like to put forward a theoretical scheme that fits very
well with ischemia basis of sporadic Alzheimer’s disease. According to our
theory, Alzheimer’s disease would start to develop when at least two
pathological events converge: brain ischemia and ischemic chronic insufficiency
of blood–brain barrier for β-amyloid
peptide [Pluta et al., 1996, Pluta et al., 2013]. These two pathologies create
two main characteristic features of Alzheimer’s disease, brain ischemia is
responsible for acute and delayed neuronal death in hippocampus and dysfunctional,
dying and dead neurons in other areas affected by ischemically induced β-amyloid peptide of the brain with
global brain atrophy, and ischemic chronic blood–brain barrier insufficiency
creating mainly amyloid pathology in surrounding brain tissue [Pluta et al.,
1996]. The magnitude and extent to which the blood–brain barrier is exposed
appears to be minimal since acute alterations such as microinfarcts were not
easily observed. Still, these neuropathology remains of great consequence to
the brain tissue and appears to be cumulative over time. Transgenic mice that
accumulate β-amyloid peptide
without neuronal loss in hippocampus support directly the above idea [Armstrong
2006]. The neuropathology of Alzheimer’s disease is rooted in ischemic
pathology what is indicated by evidence growing recently [Pluta et al., 1994a,
Qi et al., 2007, Wen et al., 2007, Pluta
et al., 2009, Kocki et al., 2015, Majd et al., 2016, Pluta et al., 2016a, Pluta
et al., 2016b, Ułamek-Kozioł et al., 2016, Fujii et al., 2017, Salminen et al.,
2017, Ułamek-Kozioł et al., 2017, Pluta et al., 2018]. The “amyloid hypothesis”
of Alzheimer’s disease and the “ischemic theory” of Alzheimer’s disease may
together explain Alzheimer’s-type neurodegeneration in the brain. Therefore,
overexpression of amyloid protein precursor gene and increased staining of its
different parts in brain after ischemia and ischemia alone probably constitute
a vicious cycle that leads to neurodegeneration with dementia. We hypothesize
that initial acute upregulation of different parts of amyloid protein precursor
in the ischemic brain is the effect of neuronal death as a response to ischemic
injury by genes associated with Alzheimer’s disease [Kocki et al., 2015, Pluta
et al., 2016a, Pluta et al., 2016b, Ułamek-Kozioł et al., 2016, Ułamek-Kozioł
et al., 2017, Pluta et al., 2018]. However, long-term overexpression of amyloid
protein precursor gene in brain may contribute to neurotoxicity. Progressing
death of neurons after ischemia–reperfusion injury may be caused not only by
degeneration of neurons destroyed during primary ischemic insult but also by
ischemic opening of blood–brain barrier with accumulation and influence of
cytotoxic fragments of amyloid protein precursor on ischemic neurons.
Ischemic
brain injury in animals causes progressive and irreversible cognitive
impairment with Alzheimer’s disease genotype and phenotype induction,
dysfunction of learning new information in the short term survival
postischemia, and memory loss in the long term survival postischemia,
suggesting that those deficits are due to impairment of memory retention or the
memory recall process [Berra de la Tremblaye, Plamondon 2011, Kiryk et al.,
2011, Li et al., 2011, Cohan et al., 2015]. Also, the progressive damage in the
hippocampus and the white matter with general brain atrophy were found,
following brain ischemia [Pluta 2000, Pluta et al., 2009]. Transient brain
ischemia resulted in an insidious delayed death of specific vulnerable
pyramidal neurons within the CA1 subfield of the hippocampus, associated with
inflammation [Sekeljic et al., 2012]. Rarefaction of white matter was noted a
few months following ischemia and markedly increased 1 year after ischemic
brain injury. White matter changes are characteristic for elderly persons and
individuals with cognitive impairment. The above changes also appear in
sporadic Alzheimer’s disease patients, suggesting that brain ischemia can be
regarded as a useful model for understanding mechanisms responsible for the
development full-blown dementia of Alzheimer’s-type [Pluta et al., 1991, Pluta
et al., 1994a, Pluta et al., 2009, Pluta et al. 2013].
CONCLUSIONS
This
review presents facts that support the hypothesis that common pathological
mechanisms to both brain ischemia and sporadic Alzheimer’s disease are
contributing to cognitive impairment and Alzheimer’s-type dementia [Berra de la
Tremblaye, Plamondon 2011, Kiryk et al., 2011, Li et al., 2011, Cohan et al.,
2015, Sherzai et al., 2018]. The main objective of this review is to increase
the knowledge on the neuronal processes underlying brain damage and their
influence on activity following neurodegeneration and their relationship with
those neuronal processes involved in cognitive decline and finally dementia.
Brain ischemia and Alzheimer’s disease share apparently common features:
characteristic genes overexpression, proteins generation, aggregation and
depositions, and specific vulnerability of certain classes of neurons, mainly
in the hippocampus and long incubation period [Pluta et al., 1994a, Pluta et
al., 1994b, Pluta 2000, Pluta 2001, Pluta et al., 2009, Pluta et al. 2013,
Kocki et al., 2015, Pluta et al., 2016a, Pluta et al., 2016b, Ułamek-Kozioł et
al., 2016, Ułamek-Kozioł et al., 2017, Pluta et al., 2018]. Development of this
fast moving and expansive field, we can study to what extent these features
reflect common etiological mechanisms. The major challenge of this novel
research strategy is, therefore, the identification of those disease relevant
molecular abnormalities and genomic and proteomic responses in the brain and
blood that require therapeutic intervention to improve the final outcome and
have influence on final ante mortem diagnosis of Alzheimer’s disease.
In future
we should study the role of pathways that are invoked during
ischemia–reperfusion injury and may potentially develop neurodegeneration in
Alzheimer’s disease brain. The fundamental message of this review is that the
neuropathology seen in Alzheimer’s disease is a continuous process starting
from the initial ischemic neuronal damage to the well-established production
and extravasations of β-amyloid
peptide from blood across dysfunctional ischemic blood–brain barrier, with
overexpression of Alzheimer’s disease-associated genes and their products in
the brain and blood, culminating in the formation of amyloid plaques and
neurofibrillary tangles and finally with development full-blown dementia of
Alzheimer’s disease phenotype.
ACKNOWLEDGMENTS
This work
was supported by the Mossakowski Medical Research Centre (T3-RP).
CONFLICT OF INTEREST
The authors declare no conflict of interest.
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