Neurodegenerative Disease Alzheimer’s Disease
changes are cumulative. Similarly, progression of plaques from a non-neuritic, diffuse appearance to one of compact deposits is suggested by the appearance of different Aβ plaque types. These include diffuse Aβ deposits, diffuse neuritic Aβ plaques, dense-core neuritic Aβ plaques, and dense core non-neuritic Aβ plaques within a single tissue section.
Neurofibrillary progression is suggested by the formation of ‘threads’ of paired helical filaments scattered within neuronal cytoplasm, along with other cells in which fully-formed tau tangles push aside the nucleus and acellular tangles that appear to have remained after the death and dissolution of a neuron.
Such progression suggests the presence of driver(s) of these events, which, even without repetition of the causative event(s) or agent(s), result in self-propagation of the neurodegenerative events that culminate in increasing densities of these neuropathological changes. This article discusses the common themes in neuropathogenesis:
• •
• potential causative factors (gene mutations and gene duplication);
risk-conferring factors (gene polymorphisms, environmental and comorbid conditions and aging); and
omnipresent glial activation and excessive expression of putative drivers (these have been found to be factors that promote furtherance of neurodegenerative events).
Causative Factors Gene Mutations—APP and PSEN1 and PSEN2 A small number of families worldwide have a high percentage of individuals who develop AD at an early age, usually well before 65 years of age, suggesting autosomal-dominant inheritance. Glenner’s discovery that the so-called senile plaques in the brain of AD patients are largely composed of Aβ highlighted the importance of this peptide in AD pathogenesis.1,2
This discovery was quickly followed by others
demonstrating the structure and size of the Aβ peptide necessary for fibril formation3,4
and mapping of the amyloid precursor protein (APP) gene for the β-amyloid precursor protein (βAPP) to chromosome (Chr) 21.5–8
The known occurrence of families with autosomal-dominantly inherited AD led to studies linking mutations in the βAPP coding region to familial AD (FAD).5,9,10
Although additional family-linked APP gene
mutations were identified in subsequent searches, they did not account for all the known familial cases. Studies of such families revealed specific mutations in two other gene sequences that are causative for AD: presenilins (PSEN) 1 and 2. These genes are located on Chr 1 (PSEN2) and Chr 14 (PSEN1).11–14
Inheritance of any one of these
autosomal-dominant, highly penetrant missense mutations in the APP or PSEN genes causes the development of early-onset AD. More recently, early-onset cases have been attributed to promoter mutations that merely elevate the expression of βAPP.15
Taken together, mutations in the APP, PSEN1, and PSEN2 genes account for the vast majority of familial cases.16
Of the three genes, the 173
recognized mutations in PSEN1 are responsible for most cases.17 Overproduction of longer forms of Aβ is the common thread between these mutations17
20 and families with them exhibit the entire array of
neuropathological changes characteristic of AD at an accelerated pace, resulting in early onset. It is notable that increased expression of βAPP is characteristic of a number of lifestyle and environmental factors associated with increased risk for later development of AD. Moreover, lifestyle risks and genetic factors are likely additive and, thus, may accelerate onset.18
Insights into the mechanistic relationships between these mutations and neuropathology have been afforded through transgenesis of mice. These have had either wild-type19 mutated PSEN1,22–25
mutated PSEN1 plus mutated βAPP,26,27
plus mutated human tau.28 glial activation,29,30 molecules31–33
or mutated human βAPP sequences,20,21 or these
Mouse models have produced evidence of as well as specific receptors and related signaling
or specific cytokines and other inflammatory factors34–36 related to Alzheimer’s pathogenesis. Such models have also been used to examine broader phenomena and potential interventions, including the protection afforded by exercise37 anti-inflammatory drugs (NSAIDs).38–43
and the benefits of non-steroidal Taken together, these findings and
the many others in which transgenic mice were used have added greatly to the understanding of molecular biological mechanisms of AD pathogenesis. They have also shown mechanisms cytokines and other factors that may act as drivers of such mechanisms.
Gene Duplications—Down Syndrome
A link between Chr-21 genes and Down syndrome (DS; trisomy 21) was suggested by the finding of Alzheimer’s-like clinical and neuropathological changes at middle age in individuals with DS.44,45
This
suggestion was further supported by mapping of the APP gene to chromosome 21.5,6,10,46,47
It is conceivable that any of the other Chr-21
More recently, duplications of the APP locus alone have been identified in French, Dutch, and Japanese pedigrees of FAD.49,50 None of the affected individuals has DS, parsing AD symptomatology with the APP gene itself. Duplication of the APP gene in either DS or FAD elevates its messenger RNA (mRNA) levels by about 50%,51
which is
consistent with faithful transcription of the 1.5-fold gene number. The steady-state levels of βAPP protein are greater than expected, however, from the 1.5-fold gene load in trisomy.5,52 until advanced age in either DS53 may even be brain-specific.55
or mouse models thereof;54
These increases do not occur the increases
These circumstances suggest that the expected increase due to gene loading is augmented by factors that act to elevate βAPP protein levels, perhaps including activated glia and the cytokines they overexpress in the mature brain.56,57
role for glia in plaque formation,58,59
genes could contribute to AD pathology in conventional cases of trisomy, but DS resulting from a partial rearrangement of Chr-21 sequences excluding the APP gene was not associated with precocious AD pathology.48
This idea, together with previous studies suggesting a is supported by a series of
investigations demonstrating the potential of these cytokines to act as generators and promoters of the neuropathological sequelae of AD, i.e.:
• Aβ plaques;60–62 • neurofibrillary tangles;63–66 • dysregulation of neurotransmitters;67 • growth factor levels;68 •
and DNA damage and neuron loss.69–72 US NEUROLOGY
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