Over a century after its first characterization, Alzheimer’s
Disease (AD) still presents a serious diagnostic and
therapeutic challenge. How pathology of AD connects to
symptomology is incompletely explained. Currently, the
pathogenic mechanisms of AD are explained primarily on
the basis of several molecular pathways, including oxidative
stress, immune response and the presence of specific genetic
variants. Moreover, treatment of the patients with AD poses
a vast challenge. There are no effective drugs to provide long
term relief of clinical symptoms of patients with this disease
or to prevent its occurrence. The present “Thematic Issue”
issue in “Current Alzheimer Research” highlights the pathogenesis
of AD, both in the neuroanatomical and symptomatic
sense, including environmental, biochemical, and genetic
factors in the clinical manifestation of this neurological disease.
We also point out to the need for new treatment methods
focused on the pathology of AD.
Underlying causes of clinical manifestations of AD are
complex, multifactorial and poorly understood. AD is the
most common cause of cognitive impairment and behavioral
changes leading to dementia. Alzheimer’s dementia is
associated with memory impairment, mainly current memory
called “fresh memory” [1, 2]. It is not known why patients
suffering from AD fail to create new memories, although
their memories of old events remain mostly unaffected.
Studies on the hippocampus of transgenic AD model showed
that impairment of memory formation correlates with
changes in glutamatergic synaptic transmission as well as
neuronal plasticity disorders [3]. Furthermore, memoryrelated
impairments associated with early AD are connected
to synaptic plasticity disorders in the cortical-hippocampal
circuits, which are also implicated in early disease
progression [4, 5]. Such preclinical stage of AD has become
an active area of recent basic and clinical research.
In this issue, we also report research on the causes of
cognitive disorders in patients with AD. According to the
currently accepted major hypothesis, AD arises mainly due
to the accumulation of extraneuronal plaques primarily
comprised of β-amyloid (Aβ) peptides, with important roles
played by intracellular neurofibrillary tangles of excessivelyphosphorylated tau protein. Such pathological aggregates
may lead to lesions first in the limbic system, hippocampus,
entorhinal cortex, and Meynert’s basal ganglia, followed by
the neocortex and the other basal ganglia. Moreover, central
deposition of aggregated proteins may lead to excitotoxicity
associated with excessive stimulation of glutamate Nmethyl-
D-aspartate (NMDA) receptors and neuronal damage
and death [6-8]. It should be emphasized that numerous
clinical trials focused on the mechanism based on the
“Amyloid Hypothesis” of AD have failed. Although it has
been previously suggested that neuronal death in AD occurs
by apoptosis or autophagy, more recent reports have
implicated neural Programmed Cell Death (PPCD) [8].
Recent failures in AD provide an opportunity in continuing
to investigate diverse approaches [9].
The thematic issue also reports other molecular factors
possibly important for the pathogenesis of Alzheimer’s
dementia among others: changes in the levels of biomarkers,
such as acetylcholine (ACh), homocysteine (Hcy),
generation of free radicals (ROS), accumulation of nuclear
(nDNA) and mitochondrial (mtDNA) DNA damages,
genetic variants and epigenetic modifications [10]. We also
recognize other impaired functioning of the cholinergic
system, including choline acetyltransferase (ChAT),
acetylcholinesterase (AChE), high-affinity choline uptake
(HACU), muscarinic (mAChR), and nicotinic (nAChR)
cholinergic receptors [11]. Current research in the cholinergic
system mainly concerns its role in modulating cognitive
functions and improving its activity through selective targeting
of mAChR and nAChR. AD also associates with severe
loss of cholinergic system activity in the brain due to the
potentially toxic interaction of tau protein with mAChR [12].
Extracellular tau may bind to mAChR, e.g., M1 and M3, and
may lead to an increase in intracellular Ca2+ concentration in
neuronal cells. The tau interaction with mAChR may also
lead to neuronal cell death. Moreover, cholinesterase
degradation is accelerated by high levels of Hcy,
hyperhomocysteinemia (HHcy).
HHcy may be an independent risk factor for both AD and
vascular dementia. Normal Hcy concentrations in cerebrospinal
fluid (CSF) slow down Aβ aggregation, while high
concentrations accelerate its aggregation [13]. HHcy may
also lead to cognitive impairment by various mechanisms,
such as disrupted nucleic acid (DNA, RNA) synthesis and
DNA repair disorders, as well as increased sensitivity of
neurons to its toxic effects [14]. Hcy may self-oxidize and increase ROS production, and additionally may lead to DNA
or protein methylation disorder, and thus affect gene
expression and enzyme activity. Moreover, there are several
genes mentioned associated with ROS generation in AD,
including: TOMM40, APOE, LPR, MAPT, APP, PSEN1 and
PSEN2 [15-17].
Another feature of AD includes mitochondrial disorders
such as increased mitophagy and mitochondrial dysfunction,
which may lead to oxidative stress generation; however, the
mechanisms that initiate these disorders are unclear [16].
Both mitochondrial dysfunction and genetic variants in the
TOMM40 and APOE genes may lead to DNA damage. On
the other hand, lowering the level of antioxidants (e.g. Glutathione,
GSH) as well as weakening the DNA repair systems,
especially in mitochondria, may lead to the development
of dementia [10, 16].
Thus, the pathogenesis of AD is a complex phenomenon
with both genetic and environmental components that remain
poorly defined. Recently emerging evidence suggests there is
also a bidirectional interaction between the intestinal
microbiota and the brain [18], and perhaps a role of
infectious agents of viral origin in AD; however, these
hypotheses require clarification.
The thematic issue also examines therapeutic strategies in
AD, including pharmacotherapy of cognitive impairment and
behavioral changes as well as other symptoms. Currently
used drugs increase cholinergic transmission or act as a
partial NMDA receptor antagonist (memantine) [19-21].
Memantine exhibits neuroprotective effects by protecting
neurons against excessive glutamatergic stimulation, reduces
the “noise” of signals in the synapses and improves the Long
Term Potentiation (LTP) process, responsible for learning.
The cholinergic drugs include Cholinesterase Inhibitors
(ChEIs) such as donepezil, rivastigmine and galantamine that
increase ACh levels by various mechanisms. Donepezil
selectively acts on AChE synthesized in neurons,
rivastigmine acts through AChE and Butyrylcholinesterase
(BuChE) synthesized in glial cells. Galantamine, in addition
to its AChE activity, has a modulating effect on nAChR.
Unfortunately, although procognitive cholinergic therapy
may lead to an increase of ACh level in the brain of AD
patients, its therapeutic effects are unclear. A fresh look at
cholinergic therapy [22] suggests that Abietane diterpenoids,
such as abietic acid, carnosic acid, and ferruginol, are
promising natural derivatives for the treatment of some
neurodegenerative diseases due to their inhibitory action on
both the AChE and BuChE. It is also important to investigate
experimental therapies directed against pathological proteins,
including the tau protein. Notably, the tau aggregation
inhibitor leuco-methylthioninium bis (hydromethanesulfonate),
LMTM may increase ACh levels in the
hippocampus and reduce spatial learning deficits based on
the studies conducted in transgenic tau expressing mice. This
gives hope for the improvement of clinical symptoms in
tauopathies [23].
Regarding genetic factors, research is being carried out
on the impact of gene variants such as ABCB1, ACE, CHAT,
CHRNA7, CYP2C9, CYP2C19, CYP2D6, CYP3A4, CYP3A5,
CYP3A7, NR1I2, NR1I3, POR, PPAR, RXR, SLC22LC1/2/5,
UGT, UGT1A9 and UGT2B7 and on the efficacy of pharmacotherapy in AD. Genetic variants of these genes may
modulate ACh formation and metabolism as well as
transport, metabolism and excretion of drugs modulating
neurotransmitter’s level. The most promising results were
demonstrated for APOE e4, the best known genetic risk
factor for dementia, BCHE-K, a reduced BuChE activity
variant and CYP2D6, a UM variant that leads to ultrafast
hepatic metabolism [24]. Furthermore, genetic factors play
an important role in inter-individual variability in drug
response [25]. Besides, epigenetic factors are also important.
Environmental factors, including early-life exposure, education,
exercise, and diet, play a crucial part in this human
disease, particularly as heterogeneous as AD [26].
Despite current available FDA-approved drugs for AD,
effective long-term pharmacotherapy of AD is currently
unknown. Hence the search and definition of effective
treatment of potential, modifiable risk factors, including
molecular ones, are becoming all the more important.
Treatment, nevertheless, may be possible based on
monoclonal antibodies that give increasing hope for the
introduction of biological treatment of AD in the near future
[27].