Monday 20 October 2003
Definition: Alzheimer disease (AD) (MIM.104300) is the most common cause of dementia in the elderly and the fourth most common cause of death in western industrialised nations.
More than 25 million people worldwide are estimated to be currently affected; however, in light of the anticipated increase in average life span, the incidence and cost of AD are predicted to quadruple within the next 50 years.
Alzheimer disease (AD) is the most common cause of dementia in the elderly and the fourth most common cause of death in western industrialised nations.
More than 25 million people worldwide are estimated to be currently affected; however, in light of the anticipated increase in average life span, the incidence and cost of AD are predicted to quadruple within the next 50 years. Thus, AD is going to become an even greater problem, highlighting the need for a better understanding of the disease and more effective methods of diagnosis and treatment.
AD is characterized by two classical hallmark pathologies in the brain:
(i) intracellular neurofibrillary tangles, composed of an abnormally phosphorylated form of the protein tau
(ii) extracellular neuritic plaques, composed of a dense amyloid core of β-amyloid peptide (Aβ) surrounded by microglia and dystrophic neurites.
Soluble oligomeric Aβ can also be found throughout the brain, and these molecules represent the potential precursors of insoluble amyloid plaques.
Most forms of AD are sporadic (i.e. idiopathic), with the onset of symptoms generally beginning after 65–70 years of age. A small proportion of cases, however, exhibit a Mendelian pattern of inheritance and are referred to as familial Alzheimer’s disease (FAD). Mutations in three different genes, APP and presenilin-1 and -2 (PSEN1 and PSEN2), are known to cause familial Alzheimer disease (FAD), which is typically characterized by the development of clinical symptoms with an early onset (<65 years of age).
The disease usually becomes clinically apparent as insidious impairment of higher intellectual function, with alterations in mood and behavior.
Later, progressive disorientation, memory loss, and aphasia indicate severe cortical dysfunction, and eventually, in 5 to 10 years, the patient becomes profoundly disabled, mute, and immobile.
Patients rarely become symptomatic before 50 years of age, but the incidence of the disease rises with age, and the prevalence roughly doubles every five years, starting from a level of 1% for the 60- to 64-year-old population and reaching 40% or more for the 85- to 89-year-old cohort.
This progressive increase in the incidence of the disease with age has given rise to major medical, social, and economic problems in countries with a growing number of elderly individuals. Most cases are sporadic, although at least 5% to 10% of cases are familial.
Pathologic changes identical to those observed in Alzheimer disease occur in almost all individuals with trisomy 21 who survive beyond 45 years, and a decline in cognition can be clinically demonstrated in many.
Although pathologic examination of brain tissue remains necessary for the definitive diagnosis of Alzheimer disease, the combination of clinical assessment and modern radiologic methods allows accurate diagnosis in 80% to 90% of cases.
The progression of Alzheimer disease is slow but relentless, with a symptomatic course often running more than 10 years. Initial symptoms are forgetfulness and other memory disturbances; with progression of the disease, other symptoms emerge, including language deficits, loss of mathematical skills, and loss of learned motor skills. In the final stages of Alzheimer disease, patients may become incontinent, mute, and unable to walk. Intercurrent disease, often pneumonia, is usually the terminal event in these individuals.
Macroscopic examination of the brain shows a variable degree of cortical atrophy with widening of the cerebral sulci that is most pronounced in the frontal, temporal, and parietal lobes. With significant atrophy, there is compensatory ventricular enlargement (hydrocephalus ex vacuo) secondary to loss of parenchyma.
The major microscopic abnormalities of Alzheimer disease are neuritic (senile) plaques, neurofibrillary tangles, and amyloid angiopathy. All of these may be present to a lesser extent in the brains of elderly nondemented individuals.
The diagnosis of Alzheimer disease is based on a combination of clinical and pathologic features. Several different diagnostic methods have been proposed, which include evaluation of different regions of the brain and various methods for estimating the frequency of plaques and tangles.
There is a fairly constant pattern of progression of involvement of brain regions: Pathologic changes (specifically plaques, tangles, and the associated neuronal loss and glial reaction) are evident earliest in the entorhinal cortex, then spread through the hippocampal formation and isocortex, and then extend into the neocortex.
Neuritic plaques are focal, spherical collections of dilated, tortuous, silver-staining neuritic processes (dystrophic neurites) often around a central amyloid core, which may be surrounded by clear halo.
Neuritic plaques range in size from 20 to 200 μm in diameter; microglial cells and reactive astrocytes are present at their periphery. Plaques can be found in the hippocampus and amygdala as well as in the neocortex, although there is usually relative sparing of primary motor and sensory cortices (this also applies to neurofibrillary tangles). Plaques can also be found in the corresponding regions of the brains of aged, nonhuman primates.
The dystrophic neurites contain paired helical filaments as well as synaptic vesicles and abnormal mitochondria. The amyloid core, which can be stained by Congo red, contains several abnormal proteins. The dominant component of the plaque core is Aβ, a peptide derived through specific processing events from a larger molecule, amyloid precursor protein (APP).
The two dominant species of Aβ, called Aβ40 and Aβ42, share an N-terminus and differ in length by two amino acids. Other proteins are present in plaques in lesser abundance, including components of the complement cascade, proinflammatory cytokines, α1-antichymotrypsin, and apolipoproteins.
Immunostaining for Aβ demonstrates the existence, in some patients, of amyloid peptide deposits in lesions lacking the surrounding neuritic reaction. These lesions, termed diffuse plaques, are found in superficial portions of cerebral cortex as well as in basal ganglia and cerebellar cortex. Diffuse plaques appear to represent an early stage of plaque development, based primarily on studies of brains from individuals with trisomy 21.
In some brain regions (cerebellar cortex and striatum), they persist as a major manifestation of the disease. They may be present in the brains of individuals with other clear-cut findings of Alzheimer disease or in isolation. While neuritic plaques contain both Aβ40 and Aβ42, diffuse plaques are predominantly made up of Aβ42.
Neurofibrillary tangles are bundles of filaments in the cytoplasm of the neurons that displace or encircle the nucleus. In pyramidal neurons, they often have an elongated "flame" shape; in rounder cells, the basket weave of fibers around the nucleus takes on a rounded contour ("globose" tangles).
Neurofibrillary tangles are visible as basophilic fibrillary structures with H & E staining but are dramatically demonstrated by silver (Bielschowsky) staining (Figs. 28-35B and 28-35C). They are commonly found in cortical neurons, especially in the entorhinal cortex, as well as in other sites such as pyramidal cells of the hippocampus, the amygdala, the basal forebrain, and the raphe nuclei.
Neurofibrillary tangles are insoluble and apparently resistant to clearance in vivo, thus remaining visible in tissue sections as "ghost" or "tombstone" tangles long after the death of the parent neuron.
Ultrastructurally, neurofibrillary tangles are composed predominantly of paired helical filaments along with some straight filaments that appear to have a comparable composition. A major component of paired helical filaments is abnormally hyperphosphorylated forms of the protein tau, an axonal microtubule-associated protein that enhances microtubule assembly.
Other antigens include MAP2 (another microtubule-associated protein) and ubiquitin. Tangles are not specific to Alzheimer disease, being found in other diseases as well. Paired helical filaments are also found in the dystrophic neurites that form the outer portions of neuritic plaques and in axons coursing through the affected gray matter as neuropil threads.
Cerebral amyloid angiopathy (CAA) is an almost invariable accompaniment of Alzheimer disease; however, it can also be found in brains of individuals without Alzheimer disease. Vascular amyloid is predominantly Aβ40, as is also true when CAA occurs without AD.
Granulovacuolar degeneration is the formation of small (∼5 μm in diameter), clear intraneuronal cytoplasmic vacuoles, each of which contains an argyrophilic granule. While it occurs with normal aging, it is most commonly found in great abundance in hippocampus and olfactory bulb in Alzheimer disease.
Hirano bodies, found especially in Alzheimer disease, are elongated, glassy, eosinophilic bodies consisting of paracrystalline arrays of beaded filaments, with actin as their major component. They are found most commonly within hippocampal pyramidal cells.
Both FAD and sporadic AD are remarkably similar and are characterized by two hallmark proteinaceous aggregates: amyloid plaques and neurofibrillary tangles (NFTs).
(1) Extracellular neuritic plaques (or amyloid plaques), composed of a dense amyloid core of β-amyloid peptide (Aβ) surrounded by microglia and dystrophic neurites. Soluble oligomeric Aβ can also be found throughout the brain, and these molecules represent the potential precursors of insoluble amyloid plaques.
Amyloid plaques are compact, spherical extracellular deposits consisting of a small (4 kDa) protein called the amyloid β-peptide (Aβ). These extracellular lesions are usually found in limbic brain regions, such as the hippocampus and amygdala, and also in specific cortical and subcortical areas. Most plaques in the AD brain are of the diffuse type, containing or surrounded by few dystrophic dendrites and axons, in contrast to the less frequent neuritic plaques, in which dystrophic neurites are a prominent and commonplace feature.
(2) intracellular neurofibrillary tangles (NFTs), composed of an abnormally phosphorylated form of the protein tau (MAPT)
Neurofibrillary tangles (NFTs) are intracellular aggregates that are composed of hyperphosphorylated forms of the tau protein. These filamentous inclusions occur in select neuronal cell bodies.
In addition to these proteinaceous aggregates, the AD brain is also marked by additional neuropathological alterations, including the loss of synapses, atrophy, the selective depletion of neurotransmitter systems (e.g. acetylcholine) and by Lewy bodies in a minority of cases.
In 25 to 40% of AD patients genetic factors are involved and in some cases, AD segregates as an autosomal dominant trait in families (familial Alzheimer disease or FAD).
In these families, 3 genes are identified that, when mutated, cause AD: the Aβ amyloid precursor protein gene (APP), the presenilin 1 gene (PSEN1) and the presenilin 2 gene (PSEN2).
Together, these mutations are responsible for 30 to 50% of autosomal dominant AD cases, and about 0.5% of AD in general.
Although mutations in the known genes are a rare cause of AD, they are important for in presymptomatic diagnostics of patients of autosomal dominant AD families that segregate these mutations. Also, the identification of these genes and mutations has been extremely important to the recent progress in the understanding of the biology of AD.
In cases where the inheritance pattern is unclear and in sporadic cases the ε4 allele of the apolipoprotein E gene (APOE) was identified as a major risk factor contributing to the pathogenesis of AD in about 20% of the cases.
However, other causative and risk genes are involved in AD and need to be identified to fully elucidate the etiology of AD. Ultimately, this will lead to the development of effective therapies for this major disease.
Familial Alzheimer disease
Like familial prion diseases, familial Alzheimer disease has an autosomal dominant pattern of inheritance. Familial Alzheimer’s disease can be caused by a mutation in the gene for amyloid precursor protein (APP), presenilin 1 (PSEN1), or presenilin 2 (PSEN2).
Cleavage of amyloid precursor protein at residue 671 by beta-secretase and at either residue 711 or residue 713 by gamma-secretase produces Abeta(1–40) (or beta40) and Abeta(1–42) (or beta42), respectively.
Abeta(1–42) forms amyloid fibrils readily and is thought to cause central nervous system dysfunction before it is deposited in plaques.
Presenilin-1 (PSEN1) and presenilin-2 (PSEN2) may form complexes with at least one other protein, nicastrin, a transmembrane neuronal glycoprotein, and these complexes may contribute to the production of Abeta(1–42).
- Epidemiological studies have shown that hypercholesterolemia is an early risk factor for the development of amyloid pathology, and other longitudinal, population-based studies have demonstrated that cholesterol is a mid- and late-life risk factor.
- The age of onset of both sporadic and familial forms of Alzheimer’s disease is modulated by allelic variants of apolipoprotein E (APOE). Three alternative allelic products of apolipoprotein E, denoted 2, 3, and 4, differ at amino acid residues 112 and 158. In many persons with two 4 alleles, Alzheimer’s disease develops at least a decade before it does in those with two copies of 2, and 3 is associated with an onset of disease at an intermediate age.
- In families with late-onset AD the risk for AD increased from 20% to 90% and mean age of onset decreased from 84 to 68 years with increasing number of apolipoprotein E epsilon 4 (APOE4) alleles.
- Overall homozygozity for APOE4 increases the relative risk by 15- to 18-fold. This makes APOE the most effective risk factor for AD aside from age. Interestingly, APOE is a lipoprotein involved in lipid trafficking between neurons and astrocytes.
apolipoprotein E type 4 locus (familail and sporadic AD)
HMGR gene locus (sporadic AD)
late-onset familial AD (LOFAD)
apolipoprotein E type 4 locus
Three pathways that are implicated in Alzheimer disease (AD) pathogenesis involve the amyloid precursor protein (APP), the microtubule-associated protein tau (TAU) and isoform 4 of cholesterol-transporting apolipoprotein E (ApoE4 from APOE).
Aberrant processing or overexpression of APP causes familial AD (FAD); mutation of TAU causes AD-like hyperphosphorylation of tau and neurofibrillary tangles (NFTs) in frontotemporal dementia (FTD) with Parkinsonism linked to chromosome 17 (FTDP-17) and ApoE4 (APOE) is a major risk factor for sporadic AD.
Deficient axonal transport
Deficient axonal transport has been implicated as a cause and a consequence of generation of amyloid β peptide (Aβ); tau (TAU) is an important regulator of axonal transport; and ApoE4 (APOE) can disrupt the neuronal cytoskeleton, which is essential for axonal transport.
Conformational instability, proteolysis, mutations and Alzheimer disease
Conformational instability can result indirectly from mutations other than those that affect the inherent stability of a neuronal protein.
The accumulation of the neurotoxic A 1-42 peptide, which gives rise to Alzheimer disease, can result from mutations that affect its catabolism , as well as mutations that increase its production from the amyloid-beta precursor protein (APP) peptides.
Similarly, in Parkinson disease, intraneuronal deposition of protein can result from loss of activity of proteolytic cofactors such as parkin, as well as mutations that directly affect the stability of alpha-synuclein (SNCA).
However, the most frequent cause of familial Alzheimer disease is mutations that allow the abnormal cleavage of APP.
Under normal conditions, this large transmembrane polypeptide is processed by the sequential action of beta- and gamma-secretases to generate the 3-kDa P3 peptide.
Alternatively, APP can be cleaved by beta- and gamma-secretases to produce a 4-kDa hydrophobic peptide that is 40-42 residues in length. This A 1-42 peptide is constitutively expressed in many tissues but, if dysregulated, it forms intraneuronal aggregates and eventually the extracellular amyloid plaques that are the central pathological feature of Alzheimer disease.
The increased production of A 1-42 can result from point mutations in the APP gene on chromosome 21 or in the presenilin-1 or presenilin-2 genes on chromosomes 14 and 1, respectively.
It has now been suggested that presenilin-1 is the gamma-secretase and that small molecule inhibitors could be developed to inhibit this enzyme and block the release of A 1-42.
The recent cloning of beta-secretase has shown it to be a novel membrane-anchored aspartyl proteinase. This enzyme is similarly amenable to the development of small molecule inhibitors that should act to reduce the production of A 1-42. The question that remains is whether or not these inhibitors can exert their effects in vivo and so prevent or retard the progression of Alzheimer disease.
The increased production of Abeta1–42 can result from point mutations in the APP gene on chromosome 21 or in the presenilin-1 or presenili-2 genes on chromosomes 14 and 1, respectively.
Presenilin 1 could be the gamma-secretase and that small molecule inhibitors could be developed to inhibit this enzyme and block the release of Abeta1–42.
The recent cloning of beta-secretase has shown it to be a novel membrane-anchored aspartyl proteinase. This enzyme is similarly amenable to the development of small molecule inhibitors that should act to reduce the production of Abeta1–42.
The question that remains is whether or not these inhibitors can exert their effects in vivo and so prevent or retard the progression of Alzheimer disease.
APP and PSENs mutations and gain- or loss-of-function properties
If APP and PSENs mutations reduce γ-secretase cleavage of APP, the proposed use of γ-secretase inhibitors as therapeutic agents in AD might lead to an unwanted enhancement of the neuronal degeneration.
Because of their dominant mode of inheritance and ability to increase the ratio of Aβ42 to Aβ40 in vitro, APP and PSENs mutations are generally considered toxic gain-of-function alleles in the context of AD pathogenesis.
However, when taking, for example, Notch signaling as a functional readout of PSENs or γ-secretase function, several studies suggest that AD-causing PSEN mutations are intrinsically at least partial loss-of-function mutations.
Indeed, loss of Notch cleavage or signaling has been demonstrated in mammalian cell lines and in Caenorhabditis elegans.
Further support for this idea comes from a strong loss-of-function mutation in the C. elegans PS homologue sel-12 (C60S), isolated in a forward genetic screen, which corresponds to the human PS1 C92S mutation and is known to cause AD by increasing the ratio of Aβ42 to Aβ40.
Nevertheless, the situation is not completely clear because, although all PSENs mutations and the partial reduction of normal PSEN1 activity increase the ratio of Aβ42 to Aβ40, the total loss of PSENs results in loss of both Aβ40 and Aβ42.
In addition, it is not well established if the increased Aβ42:Aβ40 ratio induced by the PS mutation is caused by a decrease in Aβ40, an increase in Aβ42 or a combination of both.
Interestingly, recent studies show that with respect to the generation of Aβ peptides from APP, AD-causing PS mutations have reliable loss-of-function properties.
In a recently developed, highly reproducible cellular assay, we observed that all nine tested PS mutations consistently decreased Aβ40 and accumulated direct γ-secretase substrates in the form of APP C-terminal fragments, a sign of decreased PS activity.
Although the Aβ42:Aβ40 ratio was significantly increased for all, in only four PS mutations a significant increase in Aβ42 was noted. A recent report on PS2 mutations has also shown Aβ40 loss and similar results were obtained using PS-deficient cells.
The interesting conclusion from these studies is that AD-related PS mutations are less efficient in cleaving several γ-secretase substrates including APP and therefore behave as intrinsic biological partial loss-of-function alleles regarding γ-secretase function.
Consistent with decreased γ-secretase activity for clinical AD mutations, a recent study has shown that both PS and APP mutations located in the vicinity of the γ-secretase-cleavage site reduce γ-secretase-mediated liberation of the APP C-terminal fragment.
Together these results suggest that the consistently increased Aβ42:Aβ40 ratios induced by AD-causing APP and PS mutations are the consequence of reduced γ-secretase activity. However, the exact mechanism is not understood.
protein degradation, proteasome, proteolysis
lipid metabolism, cholesterol metabolism
axonal transport, intracellualr movement
The amyloid-cascade hypothesis in mice
The amyloid-cascade hypothesis stipulates that Aβ is the trigger of all cases of AD and that the tau pathology and other degenerative changes are a downstream consequence of the Aβ pathology.
Intraneuronal Aβ accumulation appears to be an early event in the pathogenesis of AD and Down’s syndrome. In 3xTg-AD mice, the accumulation of intraneuronal Aβ precedes plaque accumulation and appears to trigger synaptic dysfunction, including alterations in LTP and paired-pulse facilitation.
Based on this hypothesis, therefore, the introduction of mutant APP or PS genes into mice should trigger a wide spectrum of AD neuropathology.
Although mutant APP or APP and PS1 mice develop extensive amyloid deposits, surprisingly, this has proven insufficient to trigger other key aspects of AD neuropathology.
Most notably, these mice lack any substantial neurofibrillary pathology. Detractors of the amyloid-cascade hypothesis point to this observation as a critical flaw of the hypothesis, although there are plausible reasons that might underlie this effect.
Neurofibrillary pathology can be modeled in mice by introducing mutations that are associated with FTDP-17 into the gene encoding tau.
These studies show that mice are capable of developing robust tau pathology. Therefore, it is unclear why APP or APP and PS1 mice fail to develop tau pathology, but perhaps the life span of mice is too short for Aβ to trigger neurofibrillary changes. Consequently, the development of mice with both hallmark lesions requires aggressive experimental strategies.
The double-transgenic APP and tau mice developed enhanced neurofibrillary pathology compared with single-mutant tau mice.
The intracranial administration of Aβ into mutant tau mice led to the generation of tangles within the amygdala. Both of these findings suggest an interaction between Aβ and tau, although the mechanism underlying this effect is unknown. Because of poor breeding, the development of a non-AD-related motor deficit and short life expectancy, these models have practical constraints that preclude their use in certain applications, such as learning and memory studies.
The removal of Aβ by immunotherapy leads to the removal of early tau pathology. The removal of both lesions is hierarchical, because after a single intrahippocampal injection of an anti-Aβ antibody, the clearance of Aβ precedes the clearance of the early tau pathology. Moreover, after the antibody itself is cleared or degraded, the Aβ pathology reemerges prior to the tau pathology. These results provide compelling evidence for the amyloid-cascade hypothesis.
Hyperphosphorylated and silver-positive tau lesions are resistant to clearance by Aβ immunotherapy. These findings are consistent with the existence of two different stages of tau pathology: an early stage, in which tau accumulates in the somatodendritic compartment, which is not stainable with the Gallyas silver-impregnation method and tau can be cleared with anti-Aβ intervention; and a late stage, in which tau is stained by Gallyas but cannot be cleared by anti-Aβ interventions. These studies also implicate the proteasome as a major factor in the clearance of the early tau lesions.
Aβ might trigger or facilitate the accumulation of tau pathology. For example, double-transgenic mice (mutant PSEN1 and mutant tau) were developed that are on the same genetic background as the 3xTg-AD mice but do not overexpress the human APP transgene and consequently do not develop any Aβ pathology.
The steady-state levels of the gene encoding tau are sixfold greater than the endogenous mouse gene, mirroring the expression level of the 3xTg-AD mice. However, the mutant PS1/tau mice develop less severe tau pathology with a later onset compared with the 3xTg-AD mice, indicating that Aβ can modulate the onset and progression of tau pathology.
Synaptic dysfunction and synpatic plasticity
Modeling both plaques and tangles in AD-relevant brain regions enables one to establish the relationship of these proteinaceous structures to crucial neurologic processes, such as learning and memory, synaptic plasticity and brain inflammation.
Spatial and contextual learning and memory is affected in the 3xTg-AD mice in an age-dependent manner and, notably, the onset of cognitive deficits occurs in advance of overt plaque and tangle pathology and is caused by the build up of intraneuronal Aβ.
Removal of this species by immunotherapy rescues the cognitive deficits, whereas these deficits retrogress once the pathology returns.
The finding that intraneuronal Aβ triggers the onset of cognitive deficits is consistent with the finding that it also induces synaptic dysfunction.
As with the onset of cognitive decline, the synaptic plasticity deficits manifest prior to the accumulation of these hallmark pathological lesions and best correlate with intraneuronal Aβ.
However, it is not yet clear whether the buildup occurs in pre- or post-synaptic cells. Overall, these findings suggest that synaptic dysfunction and cognitive decline are early events in the pathogenesis of AD. These findings are also consistent with results from another transgenic model in which synaptic deficits were found to occur independently of plaque accumulation.
To identify the molecular determinants underlying the synaptic plasticity defects, basal transmission, paired-pulse facilitation and long-term potentiation (LTP) were compared in transgenic mice with different genotypes (NonTg, PS1KI, PS1KI/tau and 3xTg-AD).
The synaptic-plasticity deficits emerge in an age-dependent manner. At one month of age, all groups showed comparable electrophysiological profiles, suggesting that the presence of the transgenes is not sufficient to alter synaptic transmission and that the mice are not born impaired.
At six months, the 3xTg-AD mice showed a profound LTP deficit, whereas the PS1KI/tau mice were unaffected, despite comparable mutant tau transgene expression between both strains; furthermore, PS1 KI mice did not show LTP deficits.
This investigation identified intraneuronal Aβ accumulation within pyramidal neurons as the best molecular candidate for triggering the onset of the synaptic deficits in the 3xTg-AD mice. This study contributes important functional significance to an emerging body of work highlighting the pathophysiological role of intraneuronal Aβ in inducing neuronal and synaptic dysfunction.
It is probable that altered tau (MAPT) will also be found to affect synaptic plasticity, although this issue has thus far not been addressed in any mutant tau transgenic mice.
axonal transport of APP influences beta-amyloid deposition and that tau regulates axonal transport. ApoE4 influences both axonal tau phosphorylation and amyloid-induced neurite pathology. (#12428809#)
Perhaps the last major hurdle that needs to be adequately addressed is the role of neuronal loss in mouse models of AD. Generally, APP-transgenic mice show little to no evidence of any cell loss, although one APP model results in significant loss. By contrast, transgenic mice that overexpress Aβ1–42 show fairly robust cell loss.
Notably, some of the tau transgenic mice show cell loss, suggesting that neurofibrillary pathology might be a requisite for neuronal loss. The extent to which neuronal loss occurs in the 3xTg-AD mice is not yet established. Early findings indicate that there is selective loss of cortical interneurons, but the reason for the loss of this particular neuronal population is not yet clear.
Mouse models (#16567017#)
Mouse models of each pathway replicate aspects of human AD but none individually displays all the hallmarks. Crossing strains to combine pathologies has been partially successful, but whether and how these pathways interact in molecular and cellular terms to cause AD remains uncertain.
β–Amyloid, tau and ApoE4 mouse models differ in many respects, but one remarkable similarity is the presence of axon pathology in each type of model. Axonal swelling and synaptic loss or dysfunction are cellular events common to each pathway in mice and to early human AD.
Reddy PH, Beal MF. Amyloid beta, mitochondrial dysfunction and synaptic damage: implications for cognitive decline in aging and Alzheimer’s disease. Trends Mol Med. 2008 Feb;14(2):45-53. PMID: #18218341#
Small DH. Network dysfunction in Alzheimer’s disease: does synaptic scaling drive disease progression? Trends Mol Med. 2008 Mar;14(3):103-8. PMID: #18262842#
Zhang YW, Xu H. Molecular and cellular mechanisms for Alzheimer’s disease: understanding APP metabolism. Curr Mol Med. 2007 Nov;7(7):687-96. PMID: #18045146#
Shen Y, He P, Zhong Z, McAllister C, Lindholm K. Distinct destructive signal pathways of neuronal death in Alzheimer’s disease. Trends Mol Med. 2006 Dec;12(12):574-9. PMID: #17055782#
McGowan E, Eriksen J, Hutton M. A decade of modeling Alzheimer’s disease in transgenic mice. Trends Genet. 2006 May;22(5):281-9. PMID: #16567017#
Slow EJ, Graham RK, Hayden MR. To be or not to be toxic: aggregations in Huntington and Alzheimer disease. Trends Genet. 2006 Aug;22(8):408-11. PMID: #16806565#
Immunology and immunotherapy of Alzheimer’s disease. Howard L. Weiner & Dan Frenkel. Nature Reviews Immunology 6, 404-416 (May 2006)
Howell N, Elson JL, Chinnery PF, Turnbull DM. mtDNA mutations and common neurodegenerative disorders. Trends Genet. 2005 Nov;21(11):583-6. PMID: #16154228#
Dermaut B, Kumar-Singh S, Rademakers R, Theuns J, Cruts M, Van Broeckhoven C. Tau is central in the genetic Alzheimer-frontotemporal dementia spectrum. Trends Genet. 2005 Dec;21(12):664-72. PMID: #16221505#
de la Torre JC. Cerebrovascular gene linked to Alzheimer’s disease pathology. Trends Mol Med. 2005 Dec;11(12):534-6. PMID: #16288900#
Hol EM, van Leeuwen FW, Fischer DF. The proteasome in Alzheimer’s disease and Parkinson’s disease: lessons from ubiquitin B+1. Trends Mol Med. 2005 Nov;11(11):488-95. PMID: #1621379021#
Vardy ER, Catto AJ, Hooper NM. Proteolytic mechanisms in amyloid-beta metabolism: therapeutic implications for Alzheimer’s disease. Trends Mol Med. 2005 Oct;11(10):464-72. PMID: #16153892#
Zhu X, Moreira PI, Smith MA, Perry G. Alzheimer’s disease: an intracellular movement disorder? Trends Mol Med. 2005 Sep;11(9):391-3. PMID: #16087404#
Laferla FM, Oddo S. Alzheimer’s disease: Abeta, tau and synaptic dysfunction. Trends Mol Med. 2005 Apr;11(4):170-6. PMID: #15823755#
Song S, Jung YK. Alzheimer’s disease meets the ubiquitin-proteasome system. Trends Mol Med. 2004 Nov;10(11):565-70. PMID: #15519283#
Cruz JC, Tsai LH. Cdk5 deregulation in the pathogenesis of Alzheimer’s disease. Trends Mol Med. 2004 Sep;10(9):452-8. PMID: #15350898#
Strategies for disease modification in Alzheimer’s disease. Martin Citron. Nature Reviews Neuroscience 5, 677-685 (September 2004)
Pathways towards and away from Alzheimer’s disease. Mark P. Mattson. Nature 430, 631-639 (5 August 2004)
Cummings JL. Alzheimer’s disease. N Engl J Med. 2004 Jul 1;351(1):56-67. PMID: #15229308#
Dickson DW. Apoptotic mechanisms in Alzheimer neurofibrillary degeneration: cause or effect? J Clin Invest. 2004 Jul;114(1):23-7. PMID: #15232608#
Streit WJ. Microglia and Alzheimer’s disease pathogenesis. J Neurosci Res. 2004 Jul 1;77(1):1-8. PMID: #15197750#
Bertram L, Tanzi RE. Alzheimer’s disease: one disorder, too many genes? Hum Mol Genet. 2004 Apr 1;13 Spec No 1:R135-41. PMID: #14764623#
Nixon RA. Niemann-Pick Type C disease and Alzheimer’s disease: the APP-endosome connection fattens up. Am J Pathol. 2004 Mar;164(3):757-61. PMID: #14982829#
Alzheimer’s disease: Mental plaque removal. Bart De Strooper and James Woodgett. Nature 423, 392-393 (22 May 2003)
Kawas CH. Early Alzheimer’s disease. N Engl J Med. 2003 Sep 11;349(11):1056-63. PMID: #12968090#
Nussbaum RL, Ellis CE. Alzheimer’s disease and Parkinson’s disease. N Engl J Med. 2003 Apr 3;348(14):1356-64. PMID: #12672864#
Poirier J. Apolipoprotein E and cholesterol metabolism in the pathogenesis and treatment of Alzheimer’s disease. Trends Mol Med. 2003 Mar;9(3):94-101. PMID: #12657430#
Calcium dyshomeostasis and intracellular signalling in alzheimer’s disease. Frank M. LaFerla. Nature Reviews Neuroscience 3, 862-872 (November 2002)
Terwel D, Dewachter I, Van Leuven F. Axonal transport, tau protein, and neurodegeneration in Alzheimer’s disease. Neuromolecular Med. 2002;2(2):151-65. PMID: #12428809#
Haass C, Steiner H. Alzheimer disease gamma-secretase: a complex story of GxGD-type presenilin proteases. Trends Cell Biol. 2002 Dec;12(12):556-62. PMID: #12495843#
McGeer PL, McGeer EG. The possible role of complement activation in Alzheimer disease. Trends Mol Med. 2002 Nov;8(11):519-23. PMID: #12421685#
Lomas DA, Carrell RW. Serpinopathies and the conformational dementias. Nat Rev Genet. 2002 Oct;3(10):759-68. PMID: #12360234#
Kurosinski P, Guggisberg M, Gotz J. Alzheimer’s and Parkinson’s disease—overlapping or synergistic pathologies? Trends Mol Med. 2002 Jan;8(1):3-5. PMID: #11796255#
Butterfield DA, Drake J, Pocernich C, Castegna A. Evidence of oxidative damage in Alzheimer’s disease brain: central role for amyloid beta-peptide. Trends Mol Med. 2001 Dec;7(12):548-54. PMID: #11733217#
Golde TE, Younkin SG. Presenilins as therapeutic targets for the treatment of Alzheimer’s disease. Trends Mol Med. 2001 Jun;7(6):264-9. PMID: #11378516#
Chapman PF, Falinska AM, Knevett SG, Ramsay MF. Genes, models and Alzheimer’s disease. Trends Genet. 2001 May;17(5):254-61. PMID: #11335035#
Herz J, Beffert U. Apolipoprotein E receptors: linking brain development and Alzheimer’s disease. Nat Rev Neurosci. 2000 Oct;1(1):51-8. PMID: #11252768#
Theuns J, Van Broeckhoven C. Transcriptional regulation of Alzheimer’s disease genes: implications for susceptibility. Hum Mol Genet. 2000 Oct;9(16):2383-94. PMID: #11005793#
Hutton M, Hardy J. The presenilins and Alzheimer’s disease. Hum Mol Genet. 1997 ;6(10):1639-46. PMID : #9300655#
Lee VM. Disruption of the cytoskeleton in Alzheimer’s disease. Curr Opin Neurobiol. 1995 Oct;5(5):663-8. PMID: #8580719#