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The latest advances in the molecular neuroscience open up some great opportunities for finally understanding the nature and finding the way to prevent neurodegenerative diseases. Among those are Alzheimer’s, Huntington’s, and Parkinson’s diseases that were previously poorly examined due to the lack of methodologies, wrong approaches, and overall ignorance in the area of neurodegeneration issues. Luckily, last decade showed the boost in the research, as the scientists were finally able to identify the genes, responsible for the occurrence of problems. They also managed to find out the protein pathways that are involved in such degenerative genes production, and according to that information about these protein pathways the first ways of treatment were introduced to the actual human medicine.

The Alzheimer’s disease is a source of the main interest for the scientists, as it is one of the most widely spread type of brain degeneration, and it is connected with the most severe ruination of cognitive functions. Patients, suffering from this terrible disease, damaging of the limbic and association cortices, become completely unable to process the new memories. This firstly concerns the common memories, but then transfers to the most valuable life details. The slow and hidden progress of inability to get the new information consistently develops in the patients, whose motor and sensory functions are not altered and who otherwise would be considered neurologically undamaged. As the time goes on, their declarative and nondeclarative memory become limited and the abilities for reasoning, abstraction, and language are fading away. This leads to a phenomenon, when function of synapses, responsible for processing new declarative memories gets interrupted, while the first amnestic symptoms start to show up without any clues of a brain injury. Later on, the scientists were able to conclude that the reason of the process is the the amyloid ? protein, a 42- residue hydrophobic peptide with an ability to congregate into long-living oligomers and polymers.

New Ways to Approach the Problem

As the researchers continue to thoroughly decode the roots of and cognitive impairments in Alzheimer’s disease, new rules and methodologies concerning the achievement of that goal start to emerge. First of all, during the very early stages of the disorder, the clinicopathological analyses should be the subject of a focus. The study of the brains of deceased patients with the minimal cognitive impairment, a very slight memory disorder that usually leads to Alzheimer’s in future, may provide far more information for the further inspection than the analysis of the brain at the late stages of Alzheimer’s. The previous researches already count a great number of data concerning the different structural and biochemical alterations that do not provide the understanding of what causes the AD-type neuronal dysfunctions. The same is applicable for dynamical examinations throughout the course of the disease. The analysis the more early stages provide the most useful information. The loss of synapse matters as well; leak of whole neurons takes place later and has lesser importance. It is also vital to use the methods that allow diagnosing functional rather than just structural alterations in the brain. The latest mouse models that coexpress transgenes encoding mutant human tau and amyloid ? protein precursor (APP) are of great value and can be used to perform in vivo electrophysiological analyses and compare the results with both behavioral and biochemical measures. It is also important to take a closer look on the studies of natural assemblies of human A? arising under physiological circumstances. Synthetic A? peptides have been used at micromolar concentrations (in contrary to the low nanomolar levels of natural A? existing in the brain and cerebrospinal fluid), and they can turn into an array of assembly forms, some of which may have biophysical features unlike those detected in vivo. Furthermore, evaluation of the effects of such synthetic aggregates is complicated, while they occur as complex mixtures that may go through quick transformations into more or less neurotoxic forms in cell culture models or upon the injection into the brain.

Synapses as the Initial Target in Alzheimer’s Disease

Early neurochemical examinations of AD brain tissue showed that the enzymes generating and metabolizing acetylcholine get exhausted. This discovery is reinforced with the fact that the most crucial damage of AD – the A? containing neuritic plaques and the tau-containing neurofibrillary tangles – are located in septalhippocampal and basal forebrain-neocortical pathways that are cholinergic, and that severe cell loss could be seen in the projection neurons of these pathways. The lack in numerous neurotransmitters grows progression of the disease, the early symptoms have connection with disorder of cholinergic and glutamatergic synapses. In addition to the transmitter alterations, many other biochemical and morphological indicators suggest that AD represents, at least initially, an attack on synapses. Of special relevance is a quantitative morphometric study of temporal and frontal cortical biopsies performed within an average of 2 to 4 years of the onset of clinical AD. This revealed a 25 to 35% decrease in the numerical density of synapses (painstakingly counted in electron micrographs) in biopsied AD cortex, and a 15 to 35% decrease in the number of synapses per cortical neuron. Even at the end of the disease, quantitative correlations of postmortem cytopathology with premortem cognitive deficits indicate that synapse loss is more robustly correlated than are numbers of plaques or tangles, degree of neuronal perikaryal loss, or extent of cortical gliosis. The degree of cognitive decline in patients with AD has been correlated with changes in the presynaptic vesicle protein synaptophysin in the hippocampus and association cortices (8–10). Indeed, synaptophysin immunoreactivity has been reported to be decreased 25% in the cortex of patients with MCI or very mild AD, relative to age-matched subjects with normal memory function. Interestingly, in some APP transgenic mouse lines, the numbers of synaptophysin-positive presynaptic terminals and microtubule-associated protein (MAP2)– positive neurons are 30% less than in nontransgenic controls at age 2 to 3 months, well before any A plaque formation (12). Comparisons of transgenic lines having varying APP expression suggest that decreases in presynaptic terminals are critically dependent on cortical A levels, not on A plaque burden or APP levels (13). In accord with this finding, presynaptic terminals are already significantly depleted in 2- to 4-month-old APP transgenic mice as their soluble A levels rise, but before A deposition (i.e., plaque formation) begins. This animal work fits nicely with growing evidence that memory and cognitive deficits in MCI and AD patients correlate far better with cortical A levels than with plaque numbers (14) and correlate best with the soluble pool of cortical A, which includes soluble oligomers (15– 17). Even in very mildly impaired patients, soluble A levels in the cortex show a significant correlation with degree of synaptic loss (17). Advances in brain imaging allow humans with very early or no amnestic symptoms to be evaluated in vivo for subtle alterations of neuronal function by positron emission tomography (PET) or functional magnetic resonance imaging (fMRI). For example, cognitively normal middle-aged and elderly subjects carrying an apolipoprotein E4 (ApoE4) allele—a strong genetic risk factor for AD—showed substantially increased hippocampal and neocortical activation by fMRI, relative to age- and education-matched non-E4 carriers, during memory tasks (18). When some of these subjects were reassessed 2 years later, the degree of baseline functional activation correlated with the degree of decline in memory. In addition, PET studies have revealed deficits in cortical glucose metabolism already in middle-aged, cognitively normal subjects with the ApoE4 allele (19). The important link here is that ApoE4 carriers undergo substantially greater accumulation of cortical A than do non-E4 carriers, and this occurs well before the development of any symptoms of AD (20) (Fig. 1).

A? Induces Changes in Synaptic Efficacy in Vivo

 The concept that progressive accumulation of A in brain regions important for memory and cognition initiates AD is currently the leading theory of causation. However, the hypothesis remains controversial, in part because a specific neurotoxic species of A and the nature of its effects on synaptic function in vivo have been ill-defined. Genetic mutations that cause aggressive, early-onset forms of AD elevate A production reviewed in (21), and certain mouse models expressing these mutations reproduce some of the cardinal neuropathological and even behavioral features of the disease e.g., (3, 22). Admittedly, current transgenic mice do not yet provide a model of full-blown AD, because they largely lack tangle formation and neuronal loss. The latter presumably represents a relatively advanced change in AD that follows synaptic dysfunction, although the long presymptomatic phase of the human disease means that both synaptic alteration and subsequent neuronal death could contribute to early symptoms. In any event, several electrophysiological studies of young mice transgenic for human APP with AD-causing mutations have revealed significant deficits in basal synaptic transmission and/or long-term potentiation Fig. 1. A hypothetical sequence of the pathogenetic steps of AD, based on currently available evidence. A-42, the 42-residue form of A. 790 25 OCTOBER 2002 VOL 298 SCIENCE www.sciencemag.org T H E D YNAMIC S YNAPSE on September 21, 2012 www.sciencemag.org Downloaded from (LTP, an electrophysiological correlate of synaptic plasticity) in the hippocampus, well before the development of microscopically detectable A deposits. For example, one study in mice bearing the Val717 3 Phe (V717F) APP mutation reported smaller excitatory postsynaptic potentials and rapid decay of LTP, relative to nontransgenic mice of matched age and genetic background, at age 4 to 5 months (23). A study in another mutant APP mouse line (Val642 3 Ile) found a similar failure to maintain LTP at age 5 to 7 months (24). In a study of a third line bearing the Lys670 3 Asn, Met671 3 Leu double mutation, no changes in basal synaptic transmission were observed at age 2 to 8 months (no A deposits) or at age 15 to 17 months (many A deposits), but hippocampal LTP measured in vivo became severely impaired by the latter age (25). The LTP deficit in these older mice was associated with impaired performance in a spatial working memory task but little or no loss of certain synaptic markers, suggesting that functional—not structural— synaptic changes were responsible for the cognitive deficits. A separate study in hippocampal slices taken from the same line found decreased basal synaptic transmission but no change in LTP at ages 12 and 18 months (26). In work on another mouse line bearing the V717F APP mutation, young animals (age 1 to 4 months) had a 40% loss in basal synaptic transmission in hippocampal slices but no change in LTP (12). By age 8 to 10 months, these mice showed an 80% deficit in synaptic transmission. Electrophysiologically, the impairment appeared to be due to a significant reduction in synaptic number, not synaptic strength, occurring between 2 and 10 months. The authors analyzed a second mouse line having lower APP transgene expression but higher A production and observed even worse synaptic transmission deficits at 2 to 4 months, again attributable to the accumulation of diffusible forms of A before plaque formation (12). Note that cortical A42 levels rise steadily in APP transgenic mice from 0.1 nmol/g cortex at 6 months (before visible deposits) to 5 nmol/g at 18 months (abundant deposits) (27). By comparison, cortical A42 levels in AD patients vary widely from 3 to 10 nmol/g at the time of death (28). Although the use of different electrophysiological protocols and mouse lines has led to some variability, all of the above studies support the concept that mutant APP transgenic mice undergo synaptic dysfunction before plaque formation. However, the nature of the synaptotoxic A species in the brain is very difficult to define, because the animals accumulate a mixture of A forms (monomers, soluble oligomers, insoluble oligomers, and some insoluble amyloid fibrils) that are likely to exist in dynamic equilibrium. In certain cultured cell lines expressing mutant human APP, natural oligomers of human A are formed soon after generation of the peptide within intracellular vesicles and are later secreted from the cell at low nanomolar levels (29). Intracerebroventricular microinjection of cell medium containing these oligomers and abundant monomers (but no amyloid fibrils) potently inhibited hippocampal LTP in adult rats. Immunodepletion from the medium of all A species abrogated the LTP block. Pretreatment of the medium with a protease that selectively degrades A monomers but not oligomers failed to prevent the LTP inhibition. Conversely, treatment of the cells with an inhibitor of -secretase (one of the two proteases that generate A from APP) markedly decreased oligomer formation at doses that still allowed appreciable monomer production, and such medium no longer disrupted LTP (29). These experiments allow inhibition of hippocampal LTP in vivo to be attributed specifically to soluble oligomers, not monomers or fibrils, of secreted human A. Synthetic A peptides can induce similar changes but generally require low micromolar doses. For example, metastable oligomers of synthetic A can cause acute electrophysiological changes in cultured neurons or hippocampal slices (30, 31). Also, microinjection of A43 plus A40 synthetic peptides into rat hippocampus led to in vivo aggregation of the peptides and the development of focal amyloid deposits that were associated with deficits in basal synaptic transmission and maintenance of LTP (32). These electrophysiological changes were accompanied by small but significant deficits in short-term (“working”) memory; long-term (“reference”) memory was unchanged (32). Therapeutic Strategies to Prevent A-induced Synaptic Dysfunction The above experimental findings have recently been complemented by manipulations intended to reduce the levels of synaptotoxic forms of A in the brains of mouse models. For example, neuron-specific postnatal inactivation of the presenilin 1 gene which encodes the probable active-site component of -secretase (21) resulted in mice with normal brain morphology in which levels of endogenous A were sharply lowered (33). Crossing such mice with mutant human APP transgenic mice yielded progeny in which no A accumulation occurred, and the LTP deficits of the latter line were rescued. This genetic lowering of -secretase activity thus mirrors the beneficial electrophysiological effects of -secretase inhibitors seen in the culture medium injection paradigm discussed above. An even more striking reversal of the synaptic dysfunction associated with soluble A assemblies was effected by single systemic injections of an antibody to A into 22-monthold APP transgenic mice (34). The impaired memory these mice showed in an object recognition task was essentially eliminated overnight, in the absence of any change in overall levels of A deposits (electrophysiological studies were not performed). If confirmed, this result strongly suggests that antibodies to A can interfere acutely with the synaptic dysfunction caused by a diffusible A species without necessarily decreasing mature, insoluble deposits.