Alzheimer's disease

ALZHEIMER'S DISEASE

Epidemiology : prevalence after age 65 : 5-10%. 15-18 million people worldwide

age 65-74 : 3%
age 75-84 : 3%
age > 85 : 47%

An estimated 4.5 million Americans have Alzheimer's disease, the most common form of dementia. The number of American's with Alzheimer's disease has more than doubled since 1980 and is projected to reach 11.3 to 16 million by the year 2050.
Aetiology :

sporadic AD (90-95%) :

obesity

acid-forming diet, such as one high in dietary fat, or to a lesser extent, total energy (caloric intake), can lead to increased serum and brain concentrations of aluminum and transition metal ions, which are implicated in oxidative stress potentially leading to the neurological damage

diabetes mellitus (vascular damage, oxidative stress, insulin replacement therapy ),

Ab interaction with receptor for advanced glycation end products (RAGE)-bearing cells in the vessel wall results in transport of Ab across the blood-brain barrier (BBB) and expression of proinflammatory cytokines and endothelin-1 (ET-1), the latter mediating Ab-induced vasoconstriction

mental activity : experts have previously suggested that keeping the mind active, through reading or crossword puzzles, can help to stave off dementia in old age. Those who develop the debilitating form of dementia are more likely to have had jobs that do not tax the brain, lending weight to the 'use it or lose it' theory. Perhaps AD has an early impact that prevents sufferers from entering mentally demanding professions such as writing, accountancy or law. But people who stimulate their minds might build up a reserve of nerve cells in the brain. Alternatively, those who exercise their grey matter might simply be better practised at thinking : this would make them more likely to perform well in the mental tests used to diagnose the disease. as people with intellectual careers tend to enjoy higher socioeconomic status, they may have better access to healthcare that may protect against AD (e.g. hormone-replacement therapy (HRT)^ref) (Smyth 498-505 )
among the more potent Ab₄₂-raising agents identified are fenofibrate , an antilipidemic agent, and celecoxib , a COX-2-selective NSAID. Many COX-2-selective NSAIDs tested raised Ab₄₂, including multiple COX-2-selective derivatives of 2 Ab₄₂-lowering NSAIDs. Compounds devoid of COX activity and the endogenous isoprenoids FPP and GGPP also raised Ab₄₂. These compounds seem to target the -secretase complex, increasing g-secretase-catalyzed production of A42 in vitro. Short-term in vivo studies show that 2 Ab₄₂-raising compounds increase Ab₄₂ levels in the brains of mice. The elevations in Ab₄₂ by these compounds are comparable to the increases in Ab₄₂ induced by Alzheimer disease-causing mutations in the genes encoding amyloid protein precursor and presenilins, raising the possibility that exogenous compounds or naturally occurring isoprenoids might increase Ab₄₂ production in humans^ref
stroke : the annual incidence for AD is 5.2% for patients, compared with 4% among those without stroke, with a RR = 1.6. The RR is significantly increased with the additional factors of systemic arterial hypertension (RR = 2.28), diabetes mellitus (RR = 4.59), or ischemic heart disease (RR = 1.95).
a transmissible CJD -like agent is prevalent in the human population^ref. Buffy coat of the blood from 5 out of 11 relatives of AD patients, including 2 with suspicious or early signs of AD, produced histologically documented spongiform encephalopathy on primary intracerebral inoculation into recipient hamsters. Material from 3 of these positives was serially transmitted in a second passage. The histological alterations observed in the brains of positive hamsters were similar to those seen in experimental CJD. These transmission results raise the intriguing possibility that CJD-like agents may be involved in at least some forms of AD^ref1,
ref2
b-methylamino L-alanine (BMAA)

inherited forms (5-10% : usually earlier onset around age 55)

dominantly inherited forms : missense mutations in

b-amyloid precursor protein (APP) / protease nexin-II (V717F, V642I, L670A, M671L). In vitro, Arctic-mutant Ab forms (proto)fibrils more effectively than wild-type Ab. Amyloid plaques form faster and are more extensive in transgenic mouse lines expressing Arctic-mutant human amyloid precursor proteins (hAPP) than in hAPP mice expressing wild-type A, even though Arctic mice have lower Ab_1-42/1-40 ratios. Thus, the Arctic mutation is highly amyloidogenic in vivo^ref.

the APP gene is located on chromosome 21 : this explains the early onset of AD in the Down's syndrome patient (100% after 45 years), who has an additional copy of chromosome 21.

presenilin 1 (PS1)
presenilin 2 (PS2)

nondominant forms

ApoE4 : individuals with apoE4e (25-33%) and CYP46*TT SNPs are more likely to develop AD. It has been shown that the efflux of cholesterol from neurons depends on the isoforms of ApoE, in the following order : ApoE2 > ApoE3 > ApoE4. As a result, the cholesterol concentration is increased in the exofacial leaflet of synaptic plasma membranes of human ApoE4 knock-in mice

strong association between the presence of HHV-1 / HSV-1 in brain and carriage of an apoE-e4 allele in the case of AD patients (even patients with Down's syndrome ) but not of controls : APP has a role in fast anterograde transport of HSV-1 from its site of synthesis in the neuronal cell body out the neuronal process to the mucosal membrane and is a major component of viral particles, at least as abundant as any viral encoded protein, and also conventional kinesin is also associated with viral particles. HHV-6 is present in a much higher proportion of the AD than of age-matched normal brains (70% vs. 40%, p=0.003) and there is extensive overlap with the presence of HSV1 in AD brains, but HHV-6, unlike HSV-1, is not directly associated in AD with apoE-e4. In 59% of the AD patients' brains harbouring HHV-6, type B is present while 38% harbour both type A and type B, and 3% type A. HHV-2 / HSV-2 is present at relatively low frequency in brains of both AD patients and normals (13% and 20%), and HHV-5 / CMV at rather higher frequencies in the two groups (36% and 35%); in neither case is the difference between the groups statistically significant. It is suggested that the striking difference in the proportion of elderly brains harbouring HSV1 and HSV2 might reflect the lower proportion of people infected with the latter, or the difference in susceptibility of the frontotemporal regions to the two viruses. In the case of HHV-6, it is not possible to exclude its presence as an opportunist, but alternatively, it might enhance the damage caused by HSV-1 and apoE-e4 in AD; in some viral diseases it is associated with characteristic brain lesions and it also augments the damage caused by certain viruses in cell culture and in animals.

decreased expression of BDNF .

Protective factors :

higher levels of serum ACE due to insertion/deletion polymorphism in intron 16
fish, whole grain cereals and vegetables consumption
cigarette smoking : nornicotine is involved in Ab glycation
people on statins are 70% less likely to be diagnosed with Alzheimer's than those who are not. In a study of 63 people with mild to moderate Alzheimer's disease, the performance of those who took atorvastatin declined less on tests of memory and brain function
the variety of leisure and physical activity one engages in -- and not its intensity in terms of calories expended - may reduce dementia risk in older people : an association between variety of activity and dementia risk, however, did not hold up in those with apoE4e^ref

Pathogenesis :

Ab is generated from :

b-amyloid precursor protein (APP) / protease nexin-II is a putative receptor for the microtubule motor kinesin, a cell surface protease inhibitor and reduces Cu : it can bind ...

a-secretase : ADAM9 cleaves at residue 671
b-secretase : b-site APP-cleaving enzyme 1 (BACE1) (whose deficiency rescues memory deficits and cholinergic dysfunction in AD-prone mouse model) and BACE2 cleaves at residue 687
g-secretase^ref : presenilin 1 (PS1) and PS2 cleaves at residue 716. PS1 is expressed at higher level. Nicastrin (Nct) / APH2, APH-1A/APH-1B, and PSENEN / PEN-2, when combined with a heterodimer of endoproteolysed presenilin fragments, form a stable, catalytically active, high-molecular-mass protein complex. This unusual aspartyl protease is the founding member of a novel class of proteases that carry out intramembrane cleavage, resulting in peptide-bond hydrolysis within the hydrophobic environs of the lipid bilayer^{ref1,
ref2,
ref3,
ref4}. These novel proteases share similar catalytic residues with hydrophilic proteases, yet have devised a creative means of introducing water within the membrane. Moreover, g-secretase's involvement in cleavage of Notch and type-I membrane receptors reveals an important role in signal transduction and developmental biology. Thus, therapeutics aimed at inhibiting g-secretase to stave off Alzheimer disease could have deleterious effects. Binding of Aph-1 and nicastrin to presenilin is an early event in gamma complex formation, providing the subcomplex with stability. Pen-2 finally activates g-secretase by an unknown mechanism. Together, these interactions prevented degradation of presenilin and facilitated its self-cleavage. We don't even know the stoichiometry of the complex, what it looks like, how active it is. There is still no structural information about this complex. Who are the immediate neighbors? How do they interact and talk to each other, and what do they do? Needless to say, an X-ray crystal structure of the complex is a long way off. What kind of abnormality in g-secretase leads to increased cleavage at the 42nd position, resulting in the amyloid b₄₂ species that more readily aggregate (cleavage at the 40th position is generally more common). Knowing this will pave the way for developing "selective" g-secretase inhibitors for treating Alzheimer disease that won't interfere with Notch function. g-secretase exhibits heterogeneous activity, with several complexes performing the same function : we're not sure if individual complexes are processing multiple substrates.

^ref

Ab_1-42 or Ab_1-43 is much more toxic than the normal Ab_1-40

carboxypeptidase B2 (plasma, carboxypeptidase U)

kallikrein 6 (neurosin, zyme)

cathepsin B1

Ab42 accumulates and oligomerizes
long-lived Ab_1-42 oligomers and polymers have subtle effects on synaptic efficacy : temporal and frontal cortical biopsies performed within an average of 2 to 4 years of the onset of clinical AD revealed a 25 to 35% decrease in the numerical density of synapses (painstakingly counted in electron micrographs) 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. Synaptophysin- and MAP2-positive neurons are 30% less in the cortex. Decreases in presynaptic terminals are critically dependent on cortial Ab levels, not on plaque burden or APP levels.
adult astrocytes (Alzheimer's cells) migrate in response to CCL-2 / MCP-1 , a chemokine present in AD lesions, cease migration upon interaction with immobilized Ab_1-42 and degrade it, implicating deficits in astroglial clearance of Ab_1-42 in the pathogenesis of AD.
an early event after exposure of postmitotic neurons to Ab is tyrosine phosphorylation of FISH adapter protein. FISH binds to and potentially regulates certain ADAM family members. FISH and ADAM12 mediate the neurotoxic effect of Ab. Expression of an ADAM12 protease-deficient mutant (ADAM12DMP) blocks Ab-induced neuronal death, and expression of an N-terminal fragment of FISH reduces A toxicity. The C-terminal fragment of FISH containing the ADAMs binding region is found to be sufficient for induction of neuronal death, which is prevented by coexpression of the ADAM12DMP. A treatment, as well as expression of the C-terminal toxic FISH fragment, induces accumulation of ADAM12 N-terminal cleavage product in conditioned medium, demonstrating activation of the ADAM metalloprotease/sheddase activity. ADAM12 protein is reduced in AD brains, pointing to a possible increase in ADAM12 proteolytic activity^ref.
Ab_1-42 oligomers gradually deposit extracellularly (amyloid plaques (AP) / argyrophil plaques / neuritic plaques (NP) / senile plaques )
extracellular proteins may aggregate through hydrophobic and electrostatic interactions facilitated by metal ions, causing AB amyloidosis . b-amyloid formation starts, or can start, extracellularly and is toxic to the surrounding neurons. The intracellular hypothesis cannot be excluded; however, so far, nobody has provided evidence for the intracellular hypothesis in vivo. Unorganized aggregation of proteins is inherently cytotoxic. Ab aggregation may induce additional toxicity in the following 2 ways:

activating microglia and astrocytes which are involved in the clearance of Ab aggregates, but also in generation of free radicals and inflammatory cytokines which could be cytotoxic
altered neuronal ionic homeostasis
accumulation of cholesterol or ceramide => oxidative injury
down-regulation of protein (peptidyl-prolyl cis/trans isomerase) NIMA-interacting 1 (PIN1) and altered GSK3b/phosphatase activities => hyperphosphorylation of microtubule-associated protein (MAP) tau causes its dissociation from microtubules and aggregation into insoluble paired helical filaments (PHF) which are the constituent of neurofibrillary tangles (NFT) (Alzheimer's neurofibrillary degeneration)

intracellular Ab₄₂, but not extracellular soluble Ab, can induce neuronal apoptosis by generating ROS, possibly via Met³⁵

mitochondrial APP occurs in a transmembrane-arrested orientation, in contact with the mitochondrial translocation complexes required for the import of proteins. Accumulation of transmembrane-arrested APP blocks protein translocation, disrupts mitochondrial function, and impairs brain energy metabolism

decrease in circulating B and CD8⁺CD28^- cells, as well as an increase in CD8⁺ cells expressing CD71⁺ and CD28⁺, was observed in AD patients. A significant decrease in IL-10 production was also found after stimulation of PMBC with Ab[1-40]. The decreased IL-10 production was not related to disease severity. The observed imbalance of immune peripheral cell subpopulations and decreased IL-10 production point to a reduction of suppressor cell function^ref

The neuropathological hallmarks of AD are the presence of > 12 amyloid plaques (AP) / argyrophil plaques / neuritic plaques (NP) / senile plaques

/ microscopic field, neurofibrillary tangles (NFT)

, synapse loss, and neuronal cell loss => gliosis in all layers of cortex. Large neurons are more affected than small ones. AD patients can also have other non specific lesions, such as granulovacuolar bodies of Simchowicz / cytoplasmic granulovacoular degeneration (GVD) (CGD)

, Hirano bodies

, Lewy bodies

and cerebral amyloid angiopathy / congophilic angiopathy. A prominent innate immune response occurs in the CNS in association with Ab deposition and plaque formation. This innate immune response includes the activation of complement, secretion of proinflammatory cytokines such as IL-1b and TNF-a; expression of the chemokines MIP-1a, MIP-1b, and MCP-1; and the secretion of NO^{ref1,
ref2,
ref3,
ref4,
ref5,
ref6}. Recent studies in transgenic mice that overexpress an AD-causing mutant form of human APP and develop amyloid deposits have revealed that crossing such mice with mice overexpressing a natural inhibitor of C3 results in worsening of Ab plaque load and more neuronal loss. This result suggests that the innate immune response found in AD and mouse models, including activation of the classical component cascade, may in part represent a beneficial response^ref. In contrast, dampening the innate immune response may also be beneficial, as a number of anti-inflamatory drugs such as those used in arthritis may delay or slow the progression of AD^ref, though these anti-inflammatory drugs may also work by targeting g-secretase^ref. Thus, it appears that Ab or its fibrillated form is refcognized in the CNS as a molecule that needs to be cleared and provokes activation of micorglia and astrocytes. If microglial or astrocytic activation fails to clear the toxic forms of Ab, the innate immune response becomes chronic and neurotoxic. On the basis of these observations, microglia or astrocytes can be modulated in 2 opposing ways to yield beneficial effects. First, one may downregulate their chronic activation and resultant injurious inflammatory response by treating with anti-inflammatory drugs. Second, one may activate them such that they clear Ab more effectively. Both CD11b⁺ and CD11c⁺ cells are localized with Ab plaques in APP transgenic (Tg) mice. Although these cells express the costimulation molecule CD86, they only express low levels of MHC II, which suggests that their function as APCs is limited^ref. The increased levels of GM-CSF that have been reported in AD^ref may contribute to differentiation of microglia into immature DC-like cells, but their full maturation may require IFN-g^ref1,
ref2. If microglia are pretreated with IFN-g, they differentiate into CD11b⁺ and CD11c⁺ cells and serve as Ab APCs for both Ab1-40 and Ab1-42 as well as support CD8-dependent proliferation of Ab-reactive T cells^ref. Ab stimulation of microglia and astrocytes leads to increased production of NO, which is toxic for neurons. Ab-stimulated microglia can also be toxic to T cells via a NO-mediated pathway^ref. This NO-mediated toxicity is enhanced in vitro by IFN-g-producing T_h1 cells and down-regulated by IL-4-, IL-10-, and TGF-b-producing T_h2 and T_h3 cells^{ref1,
ref2,
ref3}. Nonetheless, increased levels of NO in the brain of patients with AD may effectively induce apoptosis of infiltrating T cells and prevent differentiation of microglia to effective APCs. Although the CNS has been described as immunologically privileged, it is nw knwon that activated T cells routinely penetrate the CNS^{ref1,
ref2,
ref3}; however, under inflammatory conditions, T cells undergo pronounced apoptosis in the CNS^{ref1,
ref2,
ref3}. Cellular immune responses to Ab occur in middle-aged and elderly healthy subjects and patients with AD^ref. A significantly higher proportion of healthy elderly and AD subjects had strong Ab-reactive T cell responses than in middle-aged adults. Ab-reactive T cells were detected in almost all individuals tested, suggesting that these cells either escape central and peripheral tolerance or are positively selected to maintain the normal T cell repertoire. The cytokine repoertoire of these T cells was of T_h1 (proinflammatory), T_h2 (regulatory), and T_h0 (T_h1 and T_h2) phenotypes. CD4 T cells epitopes were identified primarily in the Ab15-42 peptide, which is segregated from the dominant B cell epitopes identified in Ab1-15^ref1,
ref2. MAb to DR inhibited virtually all T-cell lines tested. The analysis of Ab T-cell epitopes and their restriction to HLA-DR class II further demonstrate that Ab is processed and presented by APCs in the context of MHC and that Ab-specific T cell proliferation is mediated via MHC-TcR interactions. Thus Ab induces adaptive immune responses in the periphery in addition to innate immune responses in the CNS. It is possible that the activation and expansion of Ab-reactive T cells in the elderly and AD subjects indicate that Ab is captured by local APCs in the brain in the context of Ab deposition and that these APCs migrate to secondary lymph nodes and induce T cell activation. Although Ab deposition occurs in elderly humans that do not have overt signs of AD, there appears to be increased T cell reactivity to Ab in AD patients as, in contrast to elderly subjects, all AD patients tested had some Ab reactivity. Such reactivity could reflect an endogenous reaction to Ab deposition in the brain in the context of the local innate immune responses that occurs in AD.
Early symptoms appear to correlate with AD patients present a loss of many glutamatergic and cholinergic neurons, especially those located in the nucleus basalis of Meynert, as well as a decrease of choline acetyl transferase (ChAT) activity, which suggests that the core of the cognitive deficits of AD is caused by the loss of cholinergic input in the neocortex and allocortex (basal forebrain cholinergic neurons (BFCNs)) (transentorhinal cortex => entorhinal cortex => amygdala, nucleus basalis of Meynert, nuclei of raphe, septal-hippocampal (the center for memory processing) => temporal pole => temporal, parietal, and occipital cortex), with relatively normal levels of ChAT in a variety of brain regions : as the disease progresses deficits in numerous neurotransmitters (including CRF, SST, GABA and 5-HT) accrue
Symptoms & signs :

prodromic or reactive phase : minimal cognitive impairment (MCI) (diminishing vocabulary, causing a person to feel the desired word frustratingly 'on the tip of one's tongue', often precedes problems with sentence construction), depression, anxiety, generic memory impairment, discomforting sensation of change, social isolation, sleep disorders (> 70% : due to reduced sunlight exposure, drugs (aminophylline, antihypertensives), nycturia, depression , anxiety, pain, caffeine, ethanol , involvement of brainstem, epiphysis, and hypothalamus, and reduced responses to behavioural stimuli), maintained social and proffesional role, demential episodes (false recognitions, spatio-temporal disorientation, micturition in inappropriate places, mistakes with money, exhibitionism, ...); slowly progressive, lasting > 12 months; differential diagnosis with involutive melancholia and pseudodementia

the vocabulary of Jackson's Dilemma, published shortly before the British novelist Iris Murdoch (died in 1999) was officially diagnosed with Alzheimer's in 1995, is less rich than that of an earlier work The Sea, The Sea, published at the height of her powers in 1978. A team of British researchers made the discovery by using text-analysis software to compare the variety of words used in 3 of her novels. What's more, the rate at which new words are introduced is greater in this work and in Murdoch's 1954 first novel, Under the Net, than in Jackson's Dilemma^ref
people who will go on to develop AD display warning signs years before their official diagnosis. The signs include a worsened memory for past episodes in their own life. Unfortunately, most of these warning signs are also characteristic or normal aging. This could make it hard to diagnose the disease earlier, although the problems are worse in those who go on to be diagnosed with it. They reached the conclusions after combing through 47 AD studies from the past 20 years. The researchers crunched data from a decade’s worth of studies. This included records on 1,207 people who were later diagnosed with the disease, and 9,097 controls who stayed healthy. Scientists are investigating the disease’s pre-diagnosis stages in hopes that it might help them understand how the disease progresses, and help doctors improve treatment by catching at-risk patients earlier. The researchers said they found pre-diagnosis Alzheimer’s patients had marked deficits in overall cognitive ability, memory for episodes in their own life, speed of perceptions, and executive functioning, a set of processes that includes planning, inhibitory control and flexibility in attention. The pre-diagnosis patients showed somewhat smaller deficits in verbal ability, visuospatial skill, and attention. However, there was no deficit in their so-called primary memory, the information actively kept in mind for a task. The deficits seen in these patients mirror quite closely those seen in normal aging. Still, these problems are exacerbated in those who will go on to be diagnosed. There are no clear qualitative differences in patterns of cognitive impairment between the normal old 75-year old and the preclinical AD counterpart. Rather, we think of the normal elderly person, the preclinical AD person, and the early clinical AD patient as representing 3 instances on a continuum of cognitive capabilities. This presents an obvious challenge for accurate early diagnosis.”^ref

neuropsychiatric phase : progressively evolving dementia of the Alzheimer's type lasting 3-7 years => mental disruption; amnesia, Reich's alogic syndrome (central aphasia, agnosia and apraxia), gross mistakes and exitations in problem solving, demential logorrhea (automatic, repetitive, confabulatory language with agrammatism, paraphasias, echolalia , perseverations, use of passe-par-tout words, neologisms, ...; language may be exitating in demential mutism. Frontal impairment symptoms (attention deficit, abstract thinking deficit, alogic thought, apraxia, adynamia), Klüver-Bucy syndrome ; accessory symptoms : mood disorders (dementia with depression => frontal alteration (impulsivity, irritability, fatue and incongrous euphoria, emotional lability, apathy), obsessive phenomena (collectionism), fragmented or reversed sleep-wake rhythm, fragmentary and variable delirium (latrocinium, persecution, misery, hypochondria, jealousy => dementia with delirium), hypnagogic or hypnopompic hallucinations, afinalistic and iterative movements
neurological phase : onset of neurological signs (decline in movement and reflexes), 1 year; akinetic parkinsonian disorders (50-80%), ataxia, sphincterial disorders, onset of primitive reflexes, epilepsy, hyperkinesia, terminal adynamic syndrome
internal phase : cachexia and immunodepression lasting < 6 months => death by inanition of intervening infectious diseases

Laboratory examinations :

diagnosis (NINCD/ADRDA criteria)

definitive (AD can be confirmed only after death)
probable : clinical dementia and positive neuropsychological test, deficit > 2 cognitive areas, worsening of memory and other cognitive functions, no consciousness disturbance, age between 40 and 90, other diseases excluded
possible

cognitive tests and brain scans to assess memory-impaired patients, with about 85% accuracy. Computer analysis of language could help experts spot the warning signs earlier

¹⁸F-FDG PET of cerebral glucose metabolism is a valuable diagnostic tool for the prediction of clinical outcome in individual MCI patients. Results are superior to the exclusive assessment of the APOE genotype. A combination of both functional imaging and genotyping may allow an early high-risk or low-risk stratification of patients with either very high sensitivity or very high specificity. This may be valuable, for example, for patient selection in scientific studies^ref

cortical atrophy => ventriculomegaly (differential diagnosis with hydrocephalus)
in vivo detection of amyloid plaques :

after injection Pittsburgh Compound B (PIB) binds to amyloid plaques and can then be detected with

PET brain scan^ref
fluorescence microscopy (can only reveal 0.5 mm into the brain)

PET scan after injection of ¹¹C
MRI : a brain scan developed in mice could herald a safe and affordable way to screen patients for AD before they show any symptoms. To turn up the contrast, one atom of a non-toxic compound that is known to bind to the plaques was substituted with a derivative of fluorine that is not naturally found in mice or humans. It produces a distinctive magnetic signal that is easy to detect using MRI. When the researchers injected the compound into mice that had a condition equivalent to AD, it bound successfully to the plaques in their brains. PET scanning is being tested in clinical studies, but its resolution is limited to millimetres, and individual plaques are at least 10 times smaller than that. The use of MRI could be a better option : in addition to its high resolution, it is cheaper, more widely available and safer than PET, which requires the patient to be injected with a radioactive substance. Having shown that the MRI method works in mice, the researchers hope to be able to test the technique in humans within a few years. Before moving to clinical trials the team will need to refine the technology and the design of the compound to be absolutely sure of the method's safety

Therapy :

chemotherapy
therapeutic vaccine
gene therapy
mice with memory loss have had their condition reversed, a discovery that should help refine the search for a cure for AD and other dementias. The study also helps clarify the actual cause of dementia, which should give more focus to drug studies. The brains of people with AD's and some 50 other forms of dementia are known to have certain characteristic features, including messy bundles of fibres in nerve cells called neurofibrillary tangles. But no one has been sure whether the tangles are a cause or symptom of dementia. Mice engineered to massively overproduce a protein called tau tend to grow more of the tangles and display the same problems with memory and learning as humans with dementia : it is a certain version of the tau protein, rather than a simple over-abundance, that leads to the tangles. It has been speculated that these tau proteins, rather than the tangles, kill nerve cells. They trained mice to navigate a maze partly submerged in water, and watched for signs of memory loss. By the age of 3 months, mice genetically engineered to express 13 times too much tau protein couldn't remember the route to dry land, and had developed tangles in their brains. But surprisingly, when the researchers turned off the switch promoting tau expression, the mice began to gain back some lost memory. The performance of the 'switched-off' engineered mice was roughly half as good as their normal counterparts, and twice as good as those that continued to overproduce tau. And their performance improved even through the tangles in their brains remained. Some variety of tau proteins, and not the tangles it promotes, is responsible for dementia-related memory loss^ref. The next step is to figure out the molecular form of tau that is poisoning the neurons : that should give drug developers a better understanding of the molecules they should target. But in the context of dementia, this is just half the story. AD's patients also have plaques in their brains made of b-amyloid. Most think that this also plays a role in causing memory loss. This is a 2-protein disease

Prevention : exercise helps to flush a toxic molecule from the brain and causes a beneficial one to move in and protect nerve cells, research on mice shows. The discovery might help to explain why staying fit and keeping mentally active seem to fend off AD in humans. Experiments support the idea that exercise is a good approach to all types of problems in the brain and that a sedentary lifestyle is a risk factor. Exercise slows mental decline in mice engineered to mimic AD : exercise doubled the levels of megalin / LDL-related protein 2 (LRP2) / gp330

, a protein that helps to flush molecules thought to underlie AD out of the mice's brains and into their blood. In AD patients, amyloid-b accumulates in clumps throughout the brain. Megalin also binds to IGF in the blood and transports it to the brain : IGF is perhaps best known for bulking up muscles after exercise, but it also helps to keep nerve cells healthy. To reveal the tricks of megalin, the researchers manipulated levels of the protein in the brain of mice with AD-like disease. Artificially boosting megalin partly improved mental performance, as measured in a maze test. Levels of megalin decline with age in normal mice. The researchers suggest that this hints at a molecular link between ageing and neurodegenerative disease. But whether they will hold true remains to be seen. For brains of mice in a different model of AD, exercise does not boost levels of the protective IGF. The findings open the door to developing drugs that could boost levels of the megalin shuttle and help keep the brain healthy. The link between exercise and brain health is still not certain in humans, although the evidence is mounting up. Other research has found that staying mentally agile or even maintaining a slim physique may help to protect against AD and other brain disorders^ref.
Experimental animal models :

synthetic Ab peptides have generally been applied at mM concentrations (in contrast to the low nM levels of natural Ab found in the brain and CSF) and they can aggregate into an array of assembly forms, some of which may have biophysical properties unlike those found in vivo. Moreover, assessing the effects of such synthetic aggregates is tricky, because they occur as complex mictures and may undergo rapid transitions to more or less neurotoxic forms in cell culture models or after injection into the brain
mouse that coexpress trangenes encoding mutant human tau and APP can be used to perform in vivo electrophysiological analyses and correlate the results with both behavioral and biochemical measures, but do not yet p rovide a model of full-blown AD, because they largely lack tangle formation and neuronal loss
a transgenic mouse model that genetically mimics the arrest of Ab production expected from treatment with secretase inhibitors has been generated. These mice overexpress mutant APP from a vector that can be regulated by doxycycline. Under normal conditions, high-level expression of APP quickly induces fulminant amyloid pathology. Doxycycline administration inhibits transgenic APP expression by > 95% and reduces Ab production to levels found in nontransgenic mice. Suppression of transgenic Ab synthesis in this model abruptly halts the progression of amyloid pathology. However, formation and disaggregation of amyloid deposits appear to be in disequilibrium as the plaques require far longer to disperse than to assemble. Mice in which APP synthesis was suppressed for as long as 6 mo after the formation of Ab deposits retain a considerable amyloid load, with little sign of active clearance^ref.
loss of autophagy : protein quality-control, especially the removal of proteins with aberrant structures, has an important role in maintaining the homeostasis of non-dividing neural cells. In addition to the ubiquitin–proteasome system, emerging evidence points to the importance of autophagy—the bulk protein degradation pathway involved in starvation-induced and constitutive protein turnover—in the protein quality-control proces. However, little is known about the precise roles of autophagy in neurons. Loss of Atg7 (autophagy-related 7), a gene essential for autophagy, leads to neurodegeneration. Mice lacking Atg7 specifically in the central nervous system showed behavioural defects, including abnormal limb-clasping reflexes and a reduction in coordinated movement, and died within 28 weeks of birth. Atg7 deficiency caused massive neuronal loss in the cerebral and cerebellar cortices. Notably, polyubiquitinated proteins accumulated in autophagy-deficient neurons as inclusion bodies, which increased in size and number with ageing. There was, however, no obvious alteration in proteasome function. Autophagy is essential for the survival of neural cells, and that impairment of autophagy is implicated in the pathogenesis of neurodegenerative disorders involving ubiquitin-containing inclusion bodies^ref. Autophagy is an intracellular bulk degradation process through which a portion of the cytoplasm is delivered to lysosomes to be degraded. Although the primary role of autophagy in many organisms is in adaptation to starvation, autophagy is also thought to be important for normal turnover of cytoplasmic contents, particularly in quiescent cells such as neurons. Autophagy may have a protective role against the development of a number of neurodegenerative diseases. Loss of autophagy causes neurodegeneration even in the absence of any disease-associated mutant proteins. Mice deficient for Atg5 (autophagy-related 5) specifically in neural cells develop progressive deficits in motor function that are accompanied by the accumulation of cytoplasmic inclusion bodies in neurons. In Atg5^-/- cells, diffuse, abnormal intracellular proteins accumulate, and then form aggregates and inclusions. These results suggest that the continuous clearance of diffuse cytosolic proteins through basal autophagy is important for preventing the accumulation of abnormal proteins, which can disrupt neural function and ultimately lead to neurodegeneration^ref.

Web resources :

Alzheimer Research Forum

Usenet sci.med.diseases.alzheimer

Alzheimers news